Ebook Comprehensive Pharmacology 7 Volume Set PDF Full Chapter PDF

Comprehensive Pharmacology 7
Volume Set - eBook PDF

Visit to download the full and correct content document:
https://ebooksecure.com/download/comprehensive-pharmacology-7-volume-set-eboo
k-pdf/
COMPREHENSIVE
PHARMACOLOGY
This page intentionally left blank
COMPREHENSIVE
PHARMACOLOGY
EDITOR IN CHIEF
Terry Kenakin
Department of Pharmacology, University of North Carolina School of Medicine,
Chapel Hill, NC, United States
ASSOCIATE EDITOR IN CHIEF

Martin C. Michel
Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany
VOLUME 1
Pharmacodynamics
EDITED BY
Terry Kenakin
Department of Pharmacology, University of North Carolina School of Medicine,
Chapel Hill, NC, United States
Pharmacokinetics
EDITED BY
David S. Riddick
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge MA 02139, United States
Copyright Ó 2022 Elsevier Inc. All rights reserved
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photo-
copying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to
seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the
Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted
herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in
research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods,
compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the
safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or
damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
ISBN 978-0-12-820472-6
For information on all publications visit our website at

http://store.elsevier.com
Publisher: Oliver Walter

Acquisition Editors: Blerina Osmanaj and Kelsey Connors
Content Project Manager: Michael Nicholls
Associate Content Project Manager: Ramalakshmi Boobalan
Designer: Vicky Pearson-Esser
EDITOR IN CHIEF
Terry Kenakin received his BS in Chemistry and PhD in Pharmacology from the University of Alberta,
Canada. After a postdoctoral fellowship at University College London, UK, he moved to the United
States to take a position as a Research Scientist at Burroughs Wellcome in Research Triangle Park,
NC. After 7 years, he moved to Glaxo (now GlaxoSmithKline) where he worked for 25 years in drug
discovery. His research is on drug receptors, allosteric protein function, and the application of pharma-
cology to drug discovery. He is the Editor-in-Chief of the Journal of Receptors and Signal Transduction and
is on numerous editorial boards. He is a Fellow of the British Pharmacological Society and has received
a number of distinctions including the Goodman and Gilman award for receptor pharmacology from
ASPET, the Gaddum Memorial award from the British Pharmacological Society, and awards from the
Dutch and Norwegian pharmacology societies. He currently is a Professor of Pharmacology in the
University of North Carolina School of Medicine in Chapel Hill, NC.
v
ASSOCIATE EDITOR IN CHIEF
Martin C. Michel is a physician trained in experimental and clinical pharmacology in Essen (Germany)
and San Diego (California). He headed the Nephrology and Hypertension Research Laboratory at the
University of Essen (Germany; 1993–2002), the Department of Pharmacology & Pharmacotherapy at
the University of Amsterdam (The Netherlands; 2003–2011) and was Global Head of Product and
Pipeline Scientific Support at Boehringer Ingelheim (Germany; 2011–2016). His current affiliations
include being a Professor of Pharmacology at the Johannes Gutenberg University in Mainz (Germany;
since 2012) and being a Senior Partner at the Partnership for the Assessment and Accreditation of
Science (PAASP, Heidelberg, Germany; since 2016). His research focuses on urogenital and cardiovas-
cular pharmacology, where he has published more than 500 peer-reviewed articles cited >30,000 times.
He is editor or serves on the board of many pharmacological journals including Mol Pharmacol and
Pharmacol Rev.
vii
EDITORIAL BOARD
Editor In Chief
Terry Kenakin
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
Associate Editor In Chief
Martin C. Michel
Section Editors
Hamid Akbarali
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
Abhijit Bal
Department of Microbiology, Queen Elizabeth University Hospital, Glasgow, & Honorary Clinical Associate Professor,
University of Glasgow, United Kingdom
Kelly A. Berg
University of Texas Health San Antonio, Department of Pharmacology, San Antonio, TX, United States
Gavin Bewick
Kings College London, Diabetes Research Group, 2.21N Hodgkin Building, Guys Campus, London, United Kingdom
William P. Clarke
University of Texas Health San Antonio, Department of Pharmacology, San Antonio, TX, United States
Terry Kenakin
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
Martin C. Michel
Karnam S. Murthy
Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, United States
David S. Riddick
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
Katerina Tiligada
Department of Pharmacology, Medical School, National & Kapodistrian, University of Athens, Athens, Greece
ix
x Editorial Board
Andrew Tobin
University of Glasgow, Glasgow, United Kingdom
Elizabeth Yeh
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States
CONTRIBUTORS TO VOLUME 1
Stephen PH Alexander Lisa Cheng

Division of Physiology, Pharmacology and Neuroscience, Faculty of Pharmaceutical Sciences, The University of
School of Life Sciences, University of Nottingham British Columbia, Vancouver, BC, Canada
Medical School, Nottingham, United Kingdom
Nikki J Clauss
Mariamena Arbitrio Departments of Cellular & Integrative Physiology and
Institute of Research and Biomedical Innovation (IRIB), Pharmacology, University of Texas Health Science
Italian National Council (CNR), Secondary site of Center at San Antonio, San Antonio, TX, United States
Catanzaro, Italy
David Dahlgren
Samuel LM Arnold Department of Pharmaceutical Biosciences, Uppsala
Department of Pharmaceutics, School of Pharmacy, University, Uppsala, Sweden
University of Washington, Seattle, WA, United States;
James Dalton
and Division of Allergy and Infectious Diseases, School
Laboratory of Molecular Neuropharmacology and
of Medicine, University of Washington, Seattle, WA,
Bioinformatics, Biostatistics Unit and Institute of
United States
Neurosciences, Universitat Autònoma de Barcelona,
Erin F Barreto Bellaterra, Spain; Translational Neuroscience Unit, Parc
Department of Pharmacy, Mayo Clinic, Rochester, MN, Taulí University Hospital, Parc Taulí Research and
United States Innovation Institute (I3PT), Institute of Neurosciences,
Universitat Autònoma de Barcelona, Barcelona, Spain;
W Matthijs Blankesteijn
and Instituto de Salud Carlos III, Center for Biomedical
Department of Pharmacology&Toxicology,
Research in Mental Health Network, CIBERSAM,
Cardiovascular Research Institute Maastricht,
Madrid, Spain
Maastricht University, Maastricht, The Netherlands
Evangelos P Daskalopoulos
Gianluca Catucci
Pôle de Recherche Cardiovasculaire (CARD), Institut de
Department of Life Sciences and Systems Biology,
Recherche Expérimentale et Clinique (IREC), Université
University of Torino, Torino, Italy
catholique de Louvain (UCLouvain), Brussels, Belgium
Sergio C Chai
Lynette C Daws
Department of Chemical Biology and Therapeutics, St.
Departments of Cellular & Integrative Physiology and
Jude Children’s Research Hospital, Memphis, TN,
Pharmacology, University of Texas Health Science
United States
Center at San Antonio, San Antonio, TX, United States
Thomas KH Chang
Maria Teresa Di Martino
Faculty of Pharmaceutical Sciences, The University of
Department of Clinical and Experimental Medicine,
British Columbia, Vancouver, BC, Canada
Magna Graecia University, Catanzaro, Italy
Taosheng Chen
Dario Doller
Department of Chemical Biology and Therapeutics, St.
Alcyoneus ScienceWorks, LLC, Sparta, NJ, United States
Jude Children’s Research Hospital, Memphis, TN,
United States
xi
xii Contributors to Volume 1
Robert S Foti Margaret O James

Preclinical Development (ADME & Discovery Department of Medicinal Chemistry, University of
Toxicology), Merck & Co., Inc, Boston, MA, United Florida Academic Health Center, Gainesville, FL,
States United States
Paul K Fyfe Kelly Karl
Division of Cell Signalling and Immunology, School of Program in Molecular Biophysics and Institute for
Life Sciences, University of Dundee, Dundee, United NanoBioTechnology, Johns Hopkins University,
Kingdom Baltimore, MD, United States
Carles Gil Terry Kenakin
Laboratory of Molecular Neuropharmacology and Department of Pharmacology, University of North
Bioinformatics, Institute of Neurosciences and Carolina School of Medicine, Chapel Hill, NC, United
Department of Biochemistry & Molecular Biology, States
Universitat Autònoma de Barcelona, Bellaterra, Spain
Emily J Koubek
Gianfranco Gilardi Department of Oncology Research, Mayo Clinic,
Department of Life Sciences and Systems Biology, Rochester, MN, United States
Isaias Lans
Jesús Giraldo Laboratory of Molecular Neuropharmacology and
Laboratory of Molecular Neuropharmacology and Bioinformatics, Biostatistics Unit and Institute of
Bioinformatics, Biostatistics Unit and Institute of Neurosciences, Universitat Autònoma de Barcelona,
Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain; and Biophysics of Tropical Diseases,
Bellaterra, Spain; Translational Neuroscience Unit, Parc Max Planck Tandem Group, University of Antioquia,
Taulí University Hospital, Parc Taulí Research and Medellín, Colombia
Innovation Institute (I3PT), Institute of Neurosciences,
Thomas R Larson
Department of Molecular Pharmacology and
Experimental Therapeutics, Mayo Clinic, Rochester,
MN, United States
Madrid, Spain
Hans Lennernäs
F Peter Guengerich
Department of Pharmaceutical Biosciences, Uppsala
Department of Biochemistry, Vanderbilt University
University, Uppsala, Sweden
School of Medicine, Nashville, TN, United States
Taylor P Light
Bruno Hagenbuch
Department of Materials Science and Engineering and
Department of Pharmacology, Toxicology and
Institute for NanoBioTechnology, Johns Hopkins
Therapeutics, The University of Kansas Medical Center,
University, Baltimore, MD, United States
Kansas City, KS, United States
Eliza R McColl
Sam RJ Hoare
Department of Pharmaceutical Sciences, Leslie Dan
Pharmechanics LLC, Owego, NY, United States
Faculty of Pharmacy, University of Toronto, Toronto,
Kalina Hristova ON, Canada
Department of Materials Science and Engineering,
Alison McFarlane
Program in Molecular Biophysics and Institute for
Division of Cell Signalling and Immunology, School of
NanoBioTechnology, Johns Hopkins University,
Life Sciences, University of Dundee, Dundee, United
Baltimore, MD, United States
Kingdom
Nina Isoherranen
Thomas D Meek
Department of Pharmaceutics, School of Pharmacy,
Department of Biochemistry & Biophysics, Texas A&M
University of Washington, Seattle, WA, United States
University, College Station, TX, United States
Shinya Ito
Ignacio Moraga
Division of Clinical Pharmacology and Toxicology,
Division of Cell Signalling and Immunology, School of
Department of Pediatrics, Hospital for Sick Children,
Life Sciences, University of Dundee, Dundee, United
University of Toronto, Toronto, ON, Canada
Kingdom
Contributors to Volume 1 xiii
Jordi Ortiz Philip Sandoval

Translational Neuroscience Unit, Parc Taulí University Global Drug Metabolism and Pharmacokinetics, Takeda
Hospital, Parc Taulí Research and Innovation Institute Pharmaceutical Company Limited, Cambridge, MA,
(I3PT), Institute of Neurosciences, Universitat United States
Autònoma de Barcelona, Barcelona, Spain; Instituto de
Francesca Scionti
Salud Carlos III, Center for Biomedical Research in
Department of Clinical and Experimental Medicine,
Mental Health Network, CIBERSAM, Madrid, Spain;
Magna Graecia University, Catanzaro, Italy
and Laboratory of Molecular Neuropharmacology and
Bioinformatics, Institute of Neurosciences and Pierosandro Tagliaferri
Department of Biochemistry & Molecular Department of Clinical and Experimental Medicine,
Biology, Universitat Autònoma de Barcelona, Bellaterra, Magna Graecia University, Catanzaro, Italy
Spain
Pierfrancesco Tassone
Licia Pensabene Department of Clinical and Experimental Medicine,
Department of Medical and Surgical Science, University Magna Graecia University, Catanzaro, Italy
of Magna Graecia, Catanzaro, Italy
Rommel G Tirona
Micheline Piquette-Miller Departments of Physiology & Pharmacology and
Department of Pharmaceutical Sciences, Leslie Dan Medicine, University of Western Ontario, London, ON,
Faculty of Pharmacy, University of Toronto, Toronto, Canada
ON, Canada
Claire Townsend
Pedro Renault GlaxoSmithKline R&D, Collegeville, PA, United States
Jonathan D Tyzack
EMBL-EBI, Wellcome Genome Campus, Hinxton,
Neurosciences, Universitat Autònoma de Barcelona,
Cambridgeshire, United Kingdom
Bellaterra, Spain; Translational Neuroscience Unit, Parc
Taulí University Hospital, Parc Taulí Research and Vessela Vassileva
Innovation Institute (I3PT), Institute of Neurosciences, Department of Surgery and Cancer, Faculty of Medicine,
Universitat Autònoma de Barcelona, Barcelona, Spain; Imperial College London, London, United Kingdom
Harvey Wong
Faculty of Pharmaceutical Sciences, The University of
Madrid, Spain
British Columbia, Vancouver, BC, Canada
David S Riddick
Bin Zhou
Department of Pharmacology and Toxicology, University
of Toronto, Toronto, ON, Canada
David Roche Neurosciences, Universitat Autònoma de Barcelona,
Department of Economic and Social Sciences, Bellaterra, Spain; Translational Neuroscience Unit, Parc
International University of Catalonia, Barcelona, Taulí University Hospital, Parc Taulí Research and
Spain Innovation Institute (I3PT), Institute of Neurosciences,
Sheila J Sadeghi
Department of Life Sciences and Systems Biology,
Madrid, Spain
FOREWORD
Unlike “pure” sciences such as chemistry, biochemistry, and genetics, contemporary pharmacology draws on all of these and many
other disciplines and applies them in service of understanding and controlling physiologic processes with drugs. This amalgamation
of different approaches generates a self-reinforcing cycle in which pharmacological knowledge leads to better understanding of
physiology, which in turn enables the discovery of new drug targets and medicines to prevent, diagnose, and treat illnesses. The
development of new technologies continuously accelerates these cycles. Thus, pharmacology is tightly linked to the technological
advances applied to the study of physiology leading to an ever-changing scientific environment.
One consequence of the heterogeneity and diversity of scientific disciplines leveraged by modern pharmacologists is that it has
become almost impossible to find authoritative comprehensive collections of information on this variegated science. It is to meet
this need that Co-Editors-in-Chief Terry Kenakin and Martin Michel and a superlative cast of Section Editors and authors have
labored to create this remarkable all-encompassing compendium, Comprehensive Pharmacology. This work covers the myriad of drugs
and techniques applied to the treatment of disease. It ranges from detailed discussions of pharmacological mechanisms of drugs at
the molecular and cellular levels to the clinical application of those drugs. Encompassing 219 articles, it is arranged in volumes by
various pharmacologic disciplines (Pharmacodynamics, Pharmacokinetics, Pharmacogenomics, Drug Discovery) as well as
therapeutic areas (cardiovascular, central nervous system, cancer, gastrointestinal, immunology, endocrinology, anti-infectives)
written by leading experts in each field. The encyclopedic and detailed coverage will make this work the first stop for anyone seeking
up-to-date definitive information about essentially any topic in basic or clinical pharmacology.
Robert J. Lefkowitz, MD, Nobel laureate

Duke University School of Medicine
James B. Duke Distinguished Professor of Medicine
xvii
PREFACE
Pharmacology draws from many other disciplines including chemistry, biochemistry, anatomy, and physiology.
In contrast to those, pharmacology directly intends to better human life by improving the prevention, diagnosis,
and treatment of human disease, and sometimes even providing cure, for instance, in infectious diseases.
The past two decades have seen major achievements in science such as the sequencing of the human genome
in general and its variations between populations and individuals. Crystal structures have been resolved at high
resolution for many proteins that serve as drug targets, often even in multiple conformations. Concomitantly,
we have seen the evolvement of key novel technologies including those for analyzing and manipulating DNA
and creating novel drug candidates by combinatorial chemistry. The speed of progress has become revolu-
tionary. Accordingly, a major reference book in pharmacology today must be considerably different from those
written 15 years ago.
Defining pharmacology as the chemical control of physiology, it is a science that touches a wide realm of
other disciplines from medicine, therapeutics, physiology and just about any research endeavor that concerns
living tissue. This being the case, this present book has relevance to practitioners of medicine, bench scientists
and students at all levels from graduate to undergraduate.
The generation of useful new drugs requires not only an interaction between pharmacologists and other
scientists but also among various subspecialties within pharmacology. This includes vertical interactions, e.g.,
between medicinal chemists and clinical pharmacologists, but also horizontal interactions, e.g., between those
specializing in the pharmacology of the central nervous and the respiratory system. To enable such interactions,
scientists need sources of information that provide authoritative reviews of various techniques and fields that
allow to quickly grasp the essence of fields in which one is not an expert, but needs a critical understanding for
good inter-disciplinary work.
Comprehensive Pharmacology is an attempt to meet this need with a compendium devoted to the study and
application of drug therapy. This work reflects the myriad of drugs and techniques applied to the treatment of
disease. It ranges from detailed discussions of pharmacological mechanisms of drugs to their clinical applica-
tion. It is arranged in volumes on various pharmacologic disciplines (Pharmacodynamics, Pharmacokinetics,
Pharmacogenomics, Drug Discovery) and therapeutic areas (cardiovascular, central nervous system, cancer,
gastrointestinal, immunology, endocrinology, anti-infectives). These topics are presented by experts in each
field, and this gives the volumes much more specific discussion of the topics than any single author work. Thus,
this work provides a concise and detailed treatment of a diverse discipline.
Terry Kenakin, Editor in Chief
Martin C. Michel, Associate Editor in Chief
xix
CONTENTS OF VOLUME 1
Editor in Chief v
Associate Editor in Chief vii
Editorial Board ix
Contributors to Volume 1 xi
Foreword xv
Preface xvii
PHARMACODYNAMICS
1.01 Pharmacodynamics: Overview 1
Terry Kenakin
1.02 The Nomenclature and Standards Committee of the International Union of Basic and Clinical
Pharmacology: Achieving Consensus in Nomenclature and Championing Reproducible
Pharmacology 4
Stephen PH Alexander
1.03 Receptor Tyrosine Kinases 10
Kelly Karl, Taylor P Light, and Kalina Hristova
1.04 Cytokine Receptors 37
Alison McFarlane, Paul K Fyfe, and Ignacio Moraga
1.05 An Overview of Steady-State Enzyme Kinetics 65
Thomas D Meek
1.06 Ion Channels 118
Claire Townsend
1.07 Nuclear Receptors 151
Sergio C Chai and Taosheng Chen
1.08 Neurotransmitter Transporters and Their Role in the Pharmacological Actions of
Therapeutic and Abused Drugs 165
Nikki J Clauss and Lynette C Daws
1.09 Pharmacological Receptor Theory 205
Terry Kenakin
xix
xx Contents of Volume 1
1.10 Kinetics of Drug-Target Binding: A Guide for Drug Discovery 227

Sam RJ Hoare
1.11 Orthosteric Receptor Antagonism 272
Terry Kenakin
1.12 Allosteric Modulation 297
Dario Doller
1.13 Analysis of the Function of Receptor Oligomers by Operational Models of Agonism 337
Jesús Giraldo, Bin Zhou, David Roche, Carles Gil, Jordi Ortiz, Isaias Lans, James Dalton,
and Pedro Renault
1.14 Agonism and Biased Signaling 360
Terry Kenakin
1.15 The Pharmacology of WNT Signaling 373
Evangelos P Daskalopoulos and W Matthijs Blankesteijn
PHARMACOKINETICS
1.16 Pharmacokinetics: Overview 403
David S Riddick
1.17 Oral Drug Delivery, Absorption and Bioavailability 406
David Dahlgren and Hans Lennernäs
1.18 PK Interpretation of Drug Distribution: General Concepts and Application to
Special Populations 438
Shinya Ito
1.19 Drug Metabolism: Cytochrome P450 470
F Peter Guengerich
1.20 Drug Metabolism: Other Phase I Enzymes 509
Gianluca Catucci, Gianfranco Gilardi, and Sheila J Sadeghi
1.21 Drug Metabolism: Phase II Enzymes 563
Margaret O James
1.22 Drug TransportdUptake 585
Philip Sandoval and Bruno Hagenbuch
1.23 Drug Transporters: Efflux 608
Eliza R McColl, Vessela Vassileva, and Micheline Piquette-Miller
1.24 Drug Excretion 627
Erin F Barreto, Thomas R Larson, and Emily J Koubek
1.25 Mathematical Aspects of Clinical Pharmacokinetics 645
Rommel G Tirona
1.26 Pharmacogenetics/Pharmacogenomics of Drug-Metabolizing Enzymes and Transporters 657
Mariamena Arbitrio, Francesca Scionti, Maria Teresa Di Martino, Licia Pensabene,
Pierfrancesco Tassone, and Pierosandro Tagliaferri
1.27 Drug-Drug Interactions With a Pharmacokinetic Basis 698
Lisa Cheng, Thomas KH Chang, and Harvey Wong
Contents of Volume 1 xxi
1.28 ADME of Biologicals and New Therapeutic Modalities 716

Robert S Foti
1.29 Role of Pharmacokinetics and Pharmacokinetic Modeling in Drug Development 743
Samuel LM Arnold and Nina Isoherranen
1.30 Prediction of Drug Metabolism: Use of Structural Biology and In Silico Tools 769
Jonathan D Tyzack
1.01 Pharmacodynamics: Overview
Terry Kenakin, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
© 2022 Elsevier Inc. All rights reserved.
Reference 3
Pharmacodynamics is the study of drug-target interaction. Pharmacology is the chemical control of physiology and there are many
elements in physiological systems that qualify as drug targets; in many cases the kinetics, techniques and descriptors of these inter-
actions are unique to the type of target. For instance, membrane bound receptors are studied biochemically in soluble protein
systems, in cell membrane systems, whole cells and even structured organs. Enzymes have their own unique set of kinetic equations
that are used to characterize the interaction of both substrates and inhibitors etc. This volume discusses the various aspects of phar-
macodynamics as they pertain to different drugs and their response systems.
The main aim of pharmacodynamics is to characterize drug properties in system independent terms such that the activity of
a drug can be quantified and compared to other drugs used in therapy. Such independent scales then are used to gage drug activity
by medicinal chemists in efforts to optimize drug activity and thus improve therapy. It is important to have system-independent
scales of drug activity because drugs are rarely if ever directly first tested in the final therapeutic system. Rather, drugs are evaluated
in test systems and the data extrapolated to the therapeutic system.
This volume is divided into two principle sets of topics: (1) Drug targets and the systems utilized to quantify drug activity in
on these targets and (2) generalized techniques and concepts common to the pharmacodynamic analysis of drug activity. The
volume begins with a chapter by Stephen Alexander on The Nomenclature and Standards Committee of the International Union of
Basic and Clinical Pharmacology: Achieving Consensus in Nomenclature and Championing Reproducible Pharmacology (Chapter 1.02).
This chapter discusses a fundamental thesis in pharmacology namely the taxonomy of drugs, targets and cellular components
utilized in assessing drug activity. Traditionally pharmacologists and clinicians aimed at classifying drugs in order to simplify
their use in therapy, i.e. a ‘b-blocker’ was characterized on the basis of its affinity for the b-adrenoceptor and thus became
part of a family of other b-blockers that could be used in a variety of diseases such as hypertension and heart failure. However,
as the array of functional assays has increased through advancing technology, such simplistic classifications have become obso-
lete and actually obstructive to the effective use of drugs. Technology has been the key to the re-classification of drugs as new
assays (new eyes to see) reveal new activities that differentiate what appeared to be uniform classes of drugs. One of the first
b-blockers to be discovered is propranolol yet when tested in a new functional pharmacological assay 39 years after its discovery
propranolol was found to be an activator of ERK pathways through b-arrestin (Azzi et al., 2003). The expansion of pharmaco-
logical assays over the years has altered pre-existing simple drug taxonomy to the point where original classifications have
become blurred and much more textured than they have been. Recognition of this changing situation is important in terms
of assigning correct molecules for various pathological states.
Traditionally, the ‘low hanging fruit’ of drug targets has been G protein coupled receptors (GPCRs) which are membrane
bound receptors receiving signals from extracellular molecules and transmitting them to the cellular signaling systems in the
cell cytosol. GPCRs respond to a wide variety of stimuli from small molecules, proteins, peptides, ions and even light to
control a myriad of cell signaling cascades. GPCRs account for a large number of targets for marketed drugs and continue
to be a rich source of potential therapeutics. Pharmacological theory began with the description of drug-receptor interactions
with GPCRs and the resulting so called ‘drug receptor’ theory forms the basis of GPCR discovery programs; this is described in
Pharmacological Receptor Theory (Chapter 1.09, Terry Kenakin). This chapter describes the equations used to characterize drug
receptor interactions based on the mass action equation; these were derived utilizing the ‘receptor’ as a theoretical entity
controlling drug response. Subsequent biochemical definitions of receptors are consistent with these equations. The binding
of agonists and antagonists to receptors are described (orthosteric interactions) as well as the alteration of receptor protein
conformation (allosteric interactions) to yield fundamental molecule patterns that describe drug activity in terms of affinity
(strength of binding to the target) and efficacy (alteration of receptor state) to yield measures of drug activity that transcend
the systems where they are measured.
Traditionally GPCRs were considered to be ‘switches’ activated by hormones and neurotransmitters to give cells uniform
stimuli of varying strength. This idea emanated from the limited nature of the functional assay systems available at the time
to report cellular response due to GPCR activation. However, as the number of different assays to measure various sub-classes
of activation emerged with technology and with these advancements it became clear that GPCR activation does not uniformly
activate all cellular signaling pathways but rather different drugs produced different patterns of activation to cells, so called
‘biased signaling.’ This is described in the chapter on Agonism and Biased Signaling (Chapter 1.14, Terry Kenakin). While early
treatments of receptor-based agonism considered receptors as switches yielding homogeneous signals to cells varying only in
strength, the availability of multiple assays to measure the many effects activated receptors can have on cells clearly indicate
that the total signals emerging from agonist-activated receptors are heterogeneous and varying composition. For instance,
agonists that activate multiple pathways such as G proteins and b-arrestin show that different agonists provide different levels
Comprehensive Pharmacology, Volume 1 https://doi.org/10.1016/B978-0-12-820472-6.00194-8 1

2 Pharmacodynamics: Overview
of relative activation of these pathways. i.e. one receptor may emphasize a single pathway at the expense of another; this effect,
referred to ‘biased signaling’ has opened up new vistas for receptor signaling whereby different agonists may have efficacies that
vary in quality as well as quantity. A discussion of an important signaling pathway in cells that can be exploited therapeutically is
given for The Pharmacology of WNT Signaling (Chapter 1.15, W. Matthijs Blankesteijn).
Receptors control a large number of signaling systems in the body which support normal physiology. However, sometimes
these systems produce inappropriate signals or signals of inappropriate strength requiring modulation with antagonist drugs. It is
often important to negate such receptor-mediated activity and this is done with antagonist drugs. A large classification of these are
orthosteric antagonists which bind to the natural agonist binding site to preclude agonist binding and thus reduce agonist effect.
Such agents can be orthosteric antagonists which bind to the same binding site as the endogenous hormone or neurotransmitter
but do not produce a response; these are described in the chapter Orthosteric Receptor Antagonism (Chapter 1.11, Terry Kenakin).
This is often referred to as ‘steric hindrance’ and it can produce a range of outcomes that depend on the relative kinetics of agonist
and antagonist binding. This chapter considers the impact of these kinetics to yield either competitive, non-competitive or hemi-
equilibrium antagonism for therapeutic applications. Another mechanism whereby drugs can eliminate natural signaling is
through allostery whereby the antagonist binds to its own site on the receptor to reduce endogenous responses. In addition,
such allosteric modulators can alternatively increase failing physiological responses; this is a rapidly expanding therapeutic appli-
cation of CGPCR ligands. Allosteric mechanisms are described in the chapter Allosteric Modulation (Chapter 1.12, Dario Doller).
Part of the realization of the range of behaviors practiced by GPCRs included the fact that within the cell membrane they can form
multimeric units (usually dimers) that confer a new set of activities for drugs; this is a way cells can fine tune GPCR responses in
a cell dependent manner to invoke unique physiology when needed. GPCRs are also known to form homodimers and hetero-
dimers in the cell membrane and these new entities have different profiles of activity for drugs and physiological processes. As
such, dimers can be a unique cell-specific drug target for therapy. The process of receptor dimerization and the methods and
models used to study this mechanism and quantify the effects of drugs on the process of dimerization is given in the chapter
Analysis of the Function of Receptor Oligomers by Operational Models of Agonism (Chapter 1.13, Jesús Giraldo et al). This chapter
discusses mathematical models of dimer formation and function in terms of the current most common model for receptor func-
tion, the Black/Leff operational model. The models described include constitutive receptor activity and incorporate the allosteric
parameters known to control the interactions of receptors both with each other and with ligands. In addition, the in vitro study of
GPCR effects (an indeed drug effects on all targets) is not complete without the consideration of real time kinetics. While most
in vitro assays yield snapshots of drug activity at a prescribed time, these processes have a rate of initiation and a rate of termi-
nation that controls the magnitude of effects over a period of time. Since drugs are used in in vivo systems, drug concentration is
never constant (increasing with drug absorption and waning with drug clearance) therefore real time is critical to the magnitude
of in vivo drug effect. The consideration of kinetics in drug receptor interactions and the impact of this all-important topic on
pharmacodynamics is described in. Kinetics of Drug-Target Binding: A Guide for Drug Discovery (Chapter 1.10, Samuel Hoare).
Measurement of drug activity are often made as snapshots in time of a particular drug response. While this is useful to predict
pharmacology, the therapeutic use of drugs in vivo involves real time in that concentration is never constant and the time that the
drug associates with the target depends on kinetic parameters. Thus binding kinetics should be measured in special experiments
to yield the rate of formation of the drug-target complex (the association rate constant) and the stability of the complex (the
residence time, defined by the dissociation rate constant). This chapter discusses the models and techniques used to measure
kinetics of drug interaction and shows how kinetics impacts the value of drugs in therapeutic systems.
There are many kinds of receptors yielding a wealth of therapeutic signals to cells. One such target system is controlled by
Cytokine receptors, a unique family of receptors mediating pathological processes; these receptors are described in Cytokine
Receptors (Chapter 1.04, Ignacio Moraga), Much of the theory and modeling for pharmacology has been pioneered with
membrane bound receptors but there is a wealth of other targets available for drug therapy that currently are being exploited.
These targets have their pharmacodynamic models and systems. Thus enzymes are a rich source of drug therapeutics; this target
class and the kinetic models used to quantify their effects is given in An Overview of Steady-State Enzyme Kinetics (Chapter 1.05,
Thomas Meek). A special type of enzyme that is ubiquitous in cell signaling systems are kinases; these are described in Receptor
Tyrosine Kinases (Chapter 1.03, Kalina Hristova). Another type of unique receptor, namely nuclear receptors, control transcription
of genes in the cell nucleus and form an extremely important therapeutic target class; these are described in Nuclear Receptors
(Chapter 1.07, Taosheng Chen, Sergio Chai). Another form of signaling prevalent in cells involves the transport of ions into
and out of cells; ion channels provide this function and their role in drug therapeutics is given in Ion Channels (1.06, Claire Town-
send). Ion channels are discussed as a group of ion-transporting proteins diversified by their structures, the variety of ions they
transport, their pharmacology and the multiple modes of channel activation. While automation has allowed a broader applica-
tion of electrophysiology, this technology still has had a limited impact so far on the development of new therapeutics. This
chapter considers Ion channel structure and function (voltage-gated, ligand-gated, mechanosensor, other channel types) in terms
of functional properties (permeation and gating), intracellular and extracellular control, and ion channel pharmacology of
various ligands (antagonists, pore blockers, gating modifiers, orthosteric, negative allosteric, inverse agonists, antibodies) and
activators (agonists, channel openers, gating modifiers). The methods of studying and defining these mechanisms is considered
especially in terms of recent progress in molecular biology, genetics, structural biology, and computational methods. Finally, in
addition to ions many other important chemicals are also transported into and out of cells and these processes can be modulated
by drugs; the application of therapeutics to transporters is described in Neurotransmitter Transporters and Their Role in the Pharma-
cological Actions of Therapeutic and Abused Drugs (Chapter 1.08, Lynette Daws).
Pharmacodynamics: Overview 3
Reference
Azzi, M., Charest, P.G., Angers, S., Rousseau, G., Kohout, T., Bouvier, M., Piñeyro, G., 2003. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active
conformations for G protein-coupled receptors. Proceedings of the National Academy of Sciences of the United States of America 100, 11406–11411.This page
intentionally left blank
1.02 The Nomenclature and Standards Committee of the International Union of
Basic and Clinical Pharmacology: Achieving Consensus in Nomenclature and
Championing Reproducible Pharmacology
Stephen P.H. Alexander, Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of
Nottingham Medical School, Nottingham, United Kingdom
1.02.1 An introduction to NC-IUPHAR 4

1.02.2 Membership, aims and objectives of NC-IUPHAR 5
1.02.3 Outputs from NC-IUPHAR 5
1.02.3.1 Pharmacological reviews 6
1.02.3.2 British Journal of Pharmacology 6
1.02.3.3 The Concise Guide to Pharmacology (previously Guide to Receptors and Channels) 6
1.02.3.4 GuidetoPharmacology.org (Twitter @GuidetoPHARM) 7
1.02.4 Reflections on nomenclature successes and “failures” 7
1.02.5 Future challenges 8
Acknowledgments 8
References 9
Glossary
GtoPdb The Guide to Pharmacology database at www.GuidetoPharmacology.org.
IUPHAR The International Union of Basic and Clinical Pharmacology.
NC-IUPHAR The Nomenclature and Standards Committee of IUPHAR.
1.02.1 An introduction to NC-IUPHAR
NC-IUPHAR is the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology
(IUPHAR). IUPHAR is an umbrella organization for national and regional societies of pharmacology, with 58 affiliated societies
worldwide. It is a Scientific Union Member of the International Science Council (ICS), with an established goal to support phar-
macology research and education, and their application to improve global health.
NC-IUPHAR was established in 1987 at the Xth International Congress of Pharmacology, by the president, Sir Colin Dollery,
with the goal of issuing guidelines for the nomenclature and classification of receptors and ion channels. This has been extended
to include all the targets of current/future prescription medicines. NC-IUPHAR has addressed many important questions, issues and
controversies in pharmacology, and has overseen the development and expert-driven annotation of an authoritative and open
access, global online resource, the IUPHAR/BPS Guide to PHARMACOLOGY database (GtoPdb, see below). Since its inception,
NC-IUPHAR has had four Chairs (Table 1), who are proposed by NC-IUPHAR and validated by the Executive Committee of
IUPHAR.
To quote from our website, “NC-IUPHAR has the objectives of:
1. Issuing guidelines for the nomenclature and classification of all the (human) biological targets, including all the targets of
current and future prescription medicines;
2. Facilitating the interface between the discovery of new sequences from the Human Genome Project and the designation of the
derived entities as functional biological targets and potential drug targets;
Table 1 Chairs of NC-IUPHAR past and present.
Term Chair Location
1989–1998 Paul Vanhoutte Paris, France

1998–2002 Robert Ruffolo Collegeville, Pennsylvania, USA
2002–2014 Michael Spedding Paris, France
2015–present Stephen Alexander Nottingham, UK
4 Comprehensive Pharmacology, Volume 1 https://doi.org/10.1016/B978-0-12-820472-6.00178-X

The Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology 5
3. Designating polymorphisms and variants which are functionally important;

4. Developing an authoritative and freely available, global online resource, the IUPHAR database, accessible via the Guide to
PHARMACOLOGY portal (https://www.guidetopharmacology.org), with a remit to:
• provide access to data on all known biological targets;
• enable students and scientists in academia and industry, working in areas related to pharmacology and drug/target research,
to exploit the full potential of the considerable amount of information on drug action available in the published literature;
• provide an entry point into the pharmacological literature for basic and clinical scientists from other disciplines;
• provide an integrated educational resource with access to high quality training in the principles of basic and clinical
pharmacology and techniques;
• foster innovative drug discovery.”
NC-IUPHAR holds 1-day scientific meetings twice a year, which have been supported by unrestricted grants from Servier Labora-
tories and also, previously, the Wellcome Trust (Fig. 1). These would normally take place in either Paris or Edinburgh, where there
is high level discussion of developments across the discipline of pharmacology and updates to the IUPHAR/BPS Guide to Pharma-
cology online database, GtoPdb. In general, these meetings have a focused group of international attendees (typically 20–30) with
an over-arching theme for two sessions on the day, combined with a more general “current awareness” session. In November 2020,
a focus for the scientific symposium was fibrosis and its pharmacological/therapeutic targetting. Due to the electronic format of the
meeting, some of these talks have been made freely available for wider viewingdhttps://www.guidetopharmacology.org/
fibrosisSymposium20.jsp.
1.02.2 Membership, aims and objectives of NC-IUPHAR
Within the organization of IUPHAR, there are multiple examples of cross-linking, to which NC-IUPHAR adds considerable weight,
for example with representation from ImmuPhardthe immunopharmacology section within IUPHAR. The core of NC-IUPHAR
includes liaisons with responsibility for drug target groups (G protein-coupled receptors, nuclear hormone receptors, ligand-
gated ion channels), as well as geographical and topic constituencies (e.g. industry links and therapeutic antibodies). Ex officio
members of NC-IUPHAR provide links to the IUPHAR executive (President and Secretary-General) and other organizations,
such as the Human Genome Nomenclature Committee and IUPHAR’s Pharmacology Education Project.
A fundamental aim of NC-IUPHAR is to save pharmacologists time and energy. If we all use a logical, systematic nomenclature
for drug targets, we don’t waste time on confusion or trivia. Additionally, the involvement of human researchers and curators
ensures that selection of the “Gold Standard” compounds (see below) is critical and informed. A high value is put on evidence trian-
gulated from multiple sources to ensure the reproducibility of data.
The role of the Chair and core members of NC-iUPHAR is to coordinate the 95 subcommittees and the database curatorial
team of www.GuidetoPharmacology.org based at the University of Edinburgh (Fig. 1). As a major objective of NC-IUPHAR is to
communicate its observations, there is an editorial process linked to publications in Pharmacological Reviews and the British Jour-
nal of Pharmacology (see below and Fig. 1).
1.02.3 Outputs from NC-IUPHAR
There are four major outputs from NC-IUPHAR, which are coordinated by weekly meetings of the Chair with the curatorial team in
Edinburgh, quarterly meetings of the NC-IUPHAR Executive group and the biannual meetings of NC-IUPHAR: discussions of target
nomenclature and standards in Pharmacological Reviews; updates on pharmacological issues in the British Journal of Pharma-
cology, the GtoPdb website and the Concise Guide to Pharmacology (Fig. 1).
Fig. 1 The NC-IUPHAR network.

6 The Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology
1.02.3.1 Pharmacological reviews

From 1992 to date (mid-2021), 111 reviews have been published in Pharmacological Reviews, following an agreement with ASPET
(Fig. 2A). These IUPHAR-badged reviews are free to access and have > 43,500 citations (according to Web of Science), although
inevitably the distribution is skewed to the older publications (Fig. 2B). Generally, Pharmacol Rev reviews focus on issues of
nomenclature of drug targets, with significant “compendium” issues on voltage-gated ion channels (lead by Bill Catterall) (Catterall
et al., 2003a) and nuclear hormone receptors (lead by Vincent Laudet) (Germain et al., 2006) which have revolutionized nomen-
clature in the respective fields, as did landmark reviews on chemokine receptors (lead by Phil Murphy) (Murphy et al., 2000), and of
course, 5-HT receptors (Barnes et al., 2021).
Other publications have more generalized applications. An early review in 1996 (IUPHAR 10) focused on establishing guide-
lines for the nomenclature of new receptor subtypes (Vanhoutte et al., 1996), which aimed to present logical unifying principles
for receptor nomenclature and avoid the confusion observed when different groups applied personal preferences for names. Later,
in 2003, IUPHAR 38 updated the terms and symbols in quantitative pharmacology (Neubig et al., 2003) and in 2014, IUPHAR 90
provided recommendations for the nomenclature of receptor allosterism (Christopoulos et al., 2014).
1.02.3.2 British Journal of Pharmacology

Since 2012, NC-IUPHAR has published 31 reviews in BJP, with over 1990 citations (Fig. 2), following an agreement with the British
Pharmacological Society. The focus of reviews have been updates of the pharmacology of molecular targets with established nomen-
clature, or more diverse topics ranging from splice variants (IUPHAR 4, Bonner, 2014) to translational pharmacology (IUPHAR 6,
Dollery, 2014) to immunopharmacology (IUPHAR 16, Tiligada et al., 2015).
1.02.3.3 The Concise Guide to Pharmacology (previously Guide to Receptors and Channels)
The Concise Guide to Pharmacology is produced biennially as a special issue of the British Journal of Pharmacology. Currently, it is
the only hard copy printed by BJP. Together with a precursor, the Guide to Receptors and Channels, 10 editions (þ two online revi-
sions) have been published (Figure 4), with the most recent edition published in 2021. These have accumulated over 9250 citations,
with a mean rate in recent years of close to 2 000 citations/year. The Concise Guide is a point-in-time snapshot of 1900 molecular
12
10
Publications
8
6
2
0
Pharmacol Rev BJP

8000
6000
Citations
4000
2000
0
90
95
00
05
10
15
20
19
19
20
20
20
20
20
Year of publication
Fig. 2 Publications in Pharmacological Reviews and the British Journal of Pharmacology. Illustrated in panel A are the 111 and 31 reviews
arranged by year of publication, while panel B indicates the number of citations each review accrued up until mid-2021.
targets of drugs presented in less detail than in the online database. The intention is to highlight the pharmacology in tabular
comparisons of families of receptors, ion channels, enzymes and transporters (as well as non-classical drug targets), where the
“best” agents are listed. In this situation, “best” not only refers to the most selective agents, but a requirement for inclusion is
that these agents must be commonly available, either commercially or as a gift. There is extensive connection to original data sources
to identify the evidence base for selecting the pharmacological tools described.
The Concise Guide is freely available to download, and as a collection of PDF files on USB memory devices for distribution to
areas of the world with poor internet access.
1.02.3.4 GuidetoPharmacology.org (Twitter @GuidetoPHARM)

IUPHAR, particularly NC-IUPHAR, together with the British Pharmacological Society (BPS), have for many years run an open access
online database (IUPHAR/BPS Guide to PHARMACOLOGY database; www.guidetopharmacology.org, GtoPdb) of pharmacolog-
ical agents and their targets, together with more modest records on disease and cell types. GtoPdb is actively promulgated by the
British, American, Japanese, Indian and Chinese Pharmacological societies. Google Analytics reports over 21,000 current users
across the world (developed and developing) who between them access GtoPdb an average of 32,000 times per month.
GtoPdb provides access to expert-curated pharmacological, chemical, genetic, functional and pathophysiological data on all the
known human targets of approved and experimental drugs. The data in GtoPdb are largely derived from the primary literature,
utilizing an international network of 500 þ researchers arranged into 90 þ NC-IUPHAR subcommittees. This level of curation
together with the considered, careful advice of the expert subcommittees ensure that it has a much higher quality, in terms of accu-
racy, than resources built by algorithmic data-mining. The most recent release of the database in September 2021 included 2995
targets (approximately half of which are human proteins, but also include targets in the malaria parasites and SARS-CoV-2 virus).
We have 11,025 ligands, with 18,624 curated binding constants and 41,041 references.
It also provides an integrated educational resource with access to high quality training in the principles of basic and clinical phar-
macology and techniques through IUPHAR’s Pharmacology Education Project.
In October 2016, the IUPHAR Guide to IMMUNOPHARMACOLOGY database project (GtoImmuPdb), supported by the Well-
come Trust, was launched to address the expanding are of the pharmacology of immunity, inflammation and infection. The data in
GtoImmunPdb are fully integrated into the core GuidetoPharmacology.org database but are presented through an “immunologist-
friendly” web portal. In a similar vein, the Medicines for Malaria Venture (MMV) funded a custom portal to provide information
about antimalarials (MMV Guide to MALARIA PHARMACOLOGY).
1.02.4 Reflections on nomenclature successes and “failures”
I’d like to reflect on two areas over the last two decades, which have simplified and clarified nomenclature.
First is the story of chemokines and their receptors. Chemokines are a series of small proteins (typically < 10 kDa) associated
with the immune system, often as chemoattractants for different populations of white blood cells. Following extensive discussion
with numerous interested parties, Phil Murphy and colleagues presented an initial consensus document in 2000, which grouped
chemokines based on the number and position of conserved cysteine residues (Murphy et al., 2000). For example, CC chemokines,
such as CCL5 (alternatively known as RANTES), have two adjacent cysteine residues close to the N-terminus, while CXC chemokines
also have two cysteine residues close to the N-terminus, however, these are separated by a single amino acid (hence the “X”). These
chemokines activate a group of 20 þ G protein-coupled receptors, which had names which were uncoordinated. So just over 20
years ago, a systematic nomenclature was described linking families of receptors with the families of ligands. The nomenclature
also defined the ligands with an appropriately located “L” and receptors with an appropriately located “R.” Thus, CCR chemokine
receptors, such as CCR5, are predominantly activated by CC chemokines, such as CCL4 (less systematically known as MIP1b or
macrophage inflammatory protein 1b). CXCL8 (alternatively known as interleukin-8), on the other hand, activates primarily
CXCR1 and CXCR2 receptor.
Given that there are over 20 chemokine receptors in the human genome, the systematic nomenclature was a major task, which
has reduced uncertainty in the area considerably.
The second example of a nomenclature success is of the voltage-gated ion channels. Bill Catterall and colleagues identified
commonalities of structure of mammalian and non-mammalian channels, sufficient to describe a “chanome.” A feature of the fami-
lies of voltage-gated ion channels was a selectivity for a single ionic species, with some variation in the mechanisms of endogenous
regulation. In a series of publications (Catterall et al., 2003a, b, c; Gutman et al., 2003; Hofmann et al., 2003), they proposed that
individual voltage-gated ion channels should be identified using the chemical symbol of the principal permeating ion (Na, K, or Ca)
with the principal physiological regulator indicated as a subscript. Thus voltage-gated sodium channels have the general description
of NaV, while calcium-activated potassium channels are described as KCa. Gene families of ion channels are identified by a numerical
suffix, while a number following a decimal point defines an individual channel isoform (e.g. NaV1.1), where the numbering is orga-
nized in chronology from first identification.
While these two examples show the value of systematic nomenclature prompting widespread adoption, there are infrequent
examples where there remains inconsistent usage.
8 The Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology
One of the most studied families of G protein-coupled receptors responds to catecholamines. Very early in the history of NC-
IUPHAR, the late Paul Vanhoutte together with very eminent colleagues provided a suggestion for systematic receptor nomencla-
ture: “The receptor should be named after the endogenous agonist, or the appropriate collective term when a family of related
substances may interact with the receptor” (Vanhoutte et al., 1994).
Logically, therefore, those receptors which respond to the hormone adrenaline (epinephrine) or neurotransmitter noradrenaline
(norepinephrine) should be called “adrenaline receptors,” “noradrenaline receptors” or perhaps “catecholamine receptors”
(McGrath, 2015). As Ian McGrath noted, “adrenaline receptor” was employed by many distinguished pharmacologists up until
the early 1960s. However, the current literature reflects a mixture of usage of adrenoceptor, adrenoreceptor and adrenergic receptor
(with historical examples of epinephrinergic and norepinephrinergic receptors Aronson, 2000), each of which could be argued to be
illogical (McGrath, 2015). NC-IUPHAR prefers the use of adrenoceptors (Bylund et al., 1994), since “adrenergic” is more appropri-
ately used to described the nerves that release adrenaline. There has, however, been some division along national lines, with “adre-
noceptors” being more commonly applied in the UK, while “adrenergic receptors” is more frequent in the US.
Another long-established pharmacological target involves the actions of opiates. Over 20 years ago, a review, based on the guide-
lines from NC-IUPHAR, recommended replacement of the terms, m, d, and k for the three G protein-coupled receptors that respond
to opioids (opiate-like drugs) with the terms OP3, OP1, and OP2, respectively (Dhawan et al., 1996). However, in the three years
subsequent to the publication of this recommendation, almost all papers referring to opioid receptors continued to use the well-
established Greek symbol nomenclature, while many in the field voiced their concerns that the use of the Greek characters was so
well-established that introduction of an alternative nomenclature was both inappropriate and confusing. Indeed, it was argued that
elimination of the terminology based on the Greek symbols would lead to impaired access to, and reduced citation of, the large
body of research literature already published on the structure and properties of opioid receptors. NC-IUPHAR reconvened its opioid
receptor subcommittee in late 1999 and charged it with developing revised recommendations for the nomenclature for opioid
receptors consistent with the overall guidelines of NC-IUPHAR (Table 2) (Cox et al., 2015).
One might reflect that the pervasive influence of mobile phone communication, where (outside of the eastern Mediterranean)
use of the Greek character set would be difficult, that many pharmacologists would prefer to use mu or MOP in place of m, for
example.
Table 2 Nomenclature of opioid and opioid-related receptors (Cox et al., 2015).
Current NC-IUPHAR approved nomenclature Other (non-approved) nomenclature Examples of endogenous ligand/s
m, mu, or MOP MOR, OP3 b-Endorphin

Enkephalins
d, delta, or DOP DOR, OP1 Enkephalins
b-Endorphin
k, kappa, or KOP KOR, OP2 Dynorphin A
Dynorphin B
NOP ORL1, OP4 Nociceptin/orphanin FQ (N/OFQ)
1.02.5 Future challenges
While a substantial number of G protein-coupled receptors are established as partners of endogenous activators, about 100
members of these very successfully exploited drug targets have no established endogenous agonist or where candidates fail to
meet NC-IUPHAR’s stringent criteria for pairing (Davenport et al., 2013).
While nuclear hormone receptors are well-defined from sequence analysis of the genome, there exists a grey area for transcription
factors which are regulated by mediators which may be either endogenous or environmentally derived. These may have attributes of
receptors and are sometimes named as such, including the aryl hydrocarbon receptor, but is there a better way to classify them?
There are examples of complex pharmacology which is suggestive of a combination of receptors, often referred to as hetero-
dimers. While NC-IUPHAR has defined recommendations for nomenclature of these entities (Spedding et al., 2002), it is apparent
that receptors are often part of signaling complexes, which may involve mediator proteins, ion channels, enzymes and anchoring
proteins.
Acknowledgments
I would like to thank all the members of NC-IUPHAR past and present, as well as all the subcommittee members. In particular, I would like to thank
Michael Spedding, Jamie Davies, Arthur Christopoulos, Doriano Fabbro and Anthony Davenport as core members of NC-IUPHAR, as well as the
curatorial team from the University of Edinburgh, Elena Faccenda, Simon Harding, Chris Southan, and Adam Pawson.
References
Aronson, J.K., 2000. “Where name and image meet”dThe argument for “adrenaline”. BMJ 320, 506–509. https://www.ncbi.nlm.nih.gov/pubmed/10678871.
Barnes, N.M., Ahern, G.P., Becamel, C., Bockaert, J., Camilleri, M., et al., 2021. International union of basic and clinical pharmacology. CX. Classification of receptors for 5-
hydroxytryptamine; pharmacology and function. Pharmacological Reviews 73, 310–520. https://www.ncbi.nlm.nih.gov/pubmed/33370241.
Bonner, T.I., 2014. Should pharmacologists care about alternative splicing? IUPHAR Review 4. British Journal of Pharmacology 171, 1231–1240. https://www.ncbi.nlm.nih.gov/
pubmed/24670145.
Bylund, D.B., Eikenberg, D.C., Hieble, J.P., Langer, S.Z., Lefkowitz, R.J., et al., 1994. IV. International Union of Pharmacology nomenclature of adrenoceptors. Pharmacological
Reviews 46, 121–136. https://www.ncbi.nlm.nih.gov/pubmed/7938162.
Catterall, W.A., Chandy, K.G., Clapham, D.E., Gutman, G.A., Hofmann, F., et al., 2003a. International Union of Pharmacology: Approaches to the nomenclature of voltage-gated ion
channels. Pharmacological Reviews 55, 573–574.
Catterall, W.A., Goldin, A.L., Waxman, S.G., 2003b. International Union of Pharmacology. XXXIX. Compendium of voltage-gated ion channels: sodium channels. Pharmacological
Catterall, W.A., Striessnig, J., Snutch, T.P., Perez-Reyes, E., 2003c. International Union of Pharmacology. XL. Compendium of voltage-gated ion channels: calcium channels.
Pharmacological Reviews 55, 579–581. https://www.ncbi.nlm.nih.gov/pubmed/14657414.
Christopoulos, A., Changeux, J.P., Catterall, W.A., Fabbro, D., Burris, T.P., et al., 2014. International Union of Basic and Clinical Pharmacology. XC. Multisite pharmacology:
Recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacological Reviews 66, 918–947. https://www.ncbi.nlm.nih.gov/pubmed/
25026896.
Cox, B.M., Christie, M.J., Devi, L., Toll, L., Traynor, J.R., 2015. Challenges for opioid receptor nomenclature: IUPHAR Review 9. British Journal of Pharmacology 172, 317–323.
https://www.ncbi.nlm.nih.gov/pubmed/24528283.
Davenport, A.P., Alexander, S.P.H., Sharman, J.L., Pawson, A.J., Benson, H.E., et al., 2013. International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled
receptor list: recommendations for new pairings with cognate ligands. Pharmacological Reviews 65, 967–986. https://www.ncbi.nlm.nih.gov/pubmed/23686350.
Dhawan, B.N., Cesselin, F., Raghubir, R., Reisine, T., Bradley, P.B., et al., 1996. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacological
Dollery, C.T., 2014. Lost in Translation (LiT): IUPHAR Review 6. British Journal of Pharmacology 171, 2269–2290. https://www.ncbi.nlm.nih.gov/pubmed/24428732.
Germain, P., Staels, B., Dacquet, C., Spedding, M., Laudet, V., 2006. Overview of nomenclature of nuclear receptors. Pharmacological Reviews 58, 685–704. https://www.ncbi.
nlm.nih.gov/pubmed/17132848.
Gutman, G.A., Chandy, K.G., Adelman, J.P., Aiyar, J., Bayliss, D.A., et al., 2003. International Union of Pharmacology. XLI. Compendium of voltage-gated ion channels: Potassium
channels. Pharmacological Reviews 55, 583–586. https://www.ncbi.nlm.nih.gov/pubmed/14657415.
Hofmann, F., Biel, M., Kaupp, U.B., 2003. International Union of Pharmacology. XLII. Compendium of voltage-gated ion channels: Cyclic nucleotide-modulated channels. Phar-
macological Reviews 55, 587–589. https://www.ncbi.nlm.nih.gov/pubmed/14657416.
McGrath, J.C., 2015. Localization of a-adrenoceptors: JR Vane Medal Lecture. British Journal of Pharmacology 172, 1179–1194. https://www.ncbi.nlm.nih.gov/pubmed/
25377869.
Murphy, P.M., Baggiolini, M., Charo, I.F., Hebert, C.A., Horuk, R., et al., 2000. International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacological
Neubig, R.R., Spedding, M., Kenakin, T., Christopoulos, A., 2003. International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII.
Update on terms and symbols in quantitative pharmacology. Pharmacological Reviews 55, 597–606. https://www.ncbi.nlm.nih.gov/pubmed/14657418.
Spedding, M., Bonner, T.I., Watson, S.P., 2002. International Union of Pharmacology. XXXI. Recommendations for the nomenclature of multimeric G protein-coupled receptors.
Pharmacological Reviews 54, 231–232. https://www.ncbi.nlm.nih.gov/pubmed/12037139.
Tiligada, E., Ishii, M., Riccardi, C., Spedding, M., Simon, H.U., et al., 2015. The expanding role of immunopharmacology: IUPHAR Review 16. British Journal of Pharmacology 172,
4217–4227. https://www.ncbi.nlm.nih.gov/pubmed/26173913.
Vanhoutte, P.M., Barnard, E.A., Cosmides, G.J., Humphrey, P.P., Spedding, M., et al., 1994. I. International Union of Pharmacology Committee on RECEPTOR NOMENCLATURE AND
DRUG CLAssification. Pharmacological Reviews 46, 111–116. https://www.ncbi.nlm.nih.gov/pubmed/7938161.
Vanhoutte, P.M., Humphrey, P.P., Spedding, M., 1996. X. International Union of Pharmacology recommendations for nomenclature of new receptor subtypes. Pharmacological
1.03 Receptor Tyrosine Kinases
Kelly Karl , Taylor P. Lightb, and Kalina Hristovac, a Program in Molecular Biophysics and Institute for NanoBioTechnology, Johns
a
Hopkins University, Baltimore, MD, United States; b Department of Materials Science and Engineering and Institute for
NanoBioTechnology, Johns Hopkins University, Baltimore, MD, United States; and c Department of Materials Science and
Engineering, Program in Molecular Biophysics and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD,
United States
1.03.1 Introduction 11
1.03.2 Architecture of RTK extracellular domains 13
1.03.3 Overview of RTK kinase anatomy and function 15
1.03.4 ATP binding and the act of phosphorylation 17
1.03.4.1 Post-Kinase domains 17
1.03.4.2 Overview of ligands 18
1.03.5 Types of Inhibitors and how they work 19
1.03.5.1 TKIs 19
1.03.5.2 Antibodies 21
1.03.5.3 Aptamers 22
1.03.6 Ligand traps 22
1.03.7 RTK subfamilies and their inhibitors 23
1.03.7.1 FGF receptors 23
1.03.7.1.1 Function and dysfunction 23
1.03.7.1.2 Structure 23
1.03.7.1.3 Ligands 23
1.03.7.1.4 Inhibitors 23
1.03.7.2 ErbB (EGF) receptors 24
1.03.7.2.2 Structure 25
1.03.7.2.3 Ligands 25
1.03.7.3 VEGF receptors 25
1.03.7.3.2 Structure 26
1.03.7.3.3 Ligands 26
1.03.7.4 Eph receptors 26
1.03.7.4.2 Structure 27
1.03.7.4.3 Ligands 27
1.03.7.5 Trk receptors 28
1.03.7.5.2 Structure 28
1.03.7.5.3 Ligands 28
1.03.7.6 Insulin receptors 29
1.03.7.6.2 Structure 29
1.03.7.6.3 Ligands 29
1.03.8 Challenges, alternative strategies, and outlook 30
1.03.8.1 Enhancing specificity 30
1.03.8.2 Overcoming resistance 30
1.03.8.3 Biased inhibitors 31
1.03.8.4 Inhibitor cocktails 31
10 Comprehensive Pharmacology, Volume 1 https://doi.org/10.1016/B978-0-12-820472-6.00135-3

Receptor Tyrosine Kinases 11
1.03.9 Outlook 31
References 31
Relevant Websites 36
Glossary
Activation site A tyrosine in the activation loop that must be phosphorylated for kinase activity to occur.
Active site A region in the kinase where the phosphorylation of the substrate takes place.
Allostery A process by which biological molecules regulate their activity by transmitting the effects of binding at one site to
another site.
Angiogenesis Growth of blood vessels from pre-existing ones.
Domain A stable folded portion of a polypeptide.
Kinase An enzyme that mediates phosphorylation.
Ligand A small polypeptide that binds to the extracellular region of an RTK and activates downstream signaling.
Phosphorylation The act of adding a phosphoryl group to a substrate such as tyrosine.
1.03.1 Introduction
Receptor tyrosine kinases (RTKs) are a large family of membrane receptors that play diverse roles in human health and develop-
ment (Fantl et al., 1993; Lemmon and Schlessinger, 2010; Paul and Hristova, 2019a; Schlessinger, 2000a,b). These receptors are
expressed on the cell surface where they sense extracellular signals or “ligands” (Kufareva et al., 2017; Lemmon and Schlessinger,
2010; Murai and Pasquale, 2003). For RTKs, ligands are generally small proteins (between 50 and a few hundred amino acids
long), which are secreted by cells. The ligands bind to RTKs, promoting RTK dimerization and in some cases, oligomerization,
which brings the two kinase domains in close proximity. As a result, the kinases phosphorylate each other to activate each other.
The activated kinases bind and phosphorylate cytoplasmic effector proteins, triggering cascades of phosphorylation events that
control cell growth, differentiation, migration, metabolism, and survival (Lemmon and Schlessinger, 2010; Schlessinger,
2000a,b). RTKs share a similar general architecture as they all consist of an extracellular (EC) region, a single-pass transmembrane
(TM) helix, and an intracellular (IC) region (Fig. 1) (Lemmon and Schlessinger, 2010; Schlessinger, 2000a,b; Trenker and Jura,
2020). Members of the RTK family are subdivided into 20 subfamilies according to their sequence and structural properties along
with their ligand binding partners.
RTK extracellular regions are different between subfamilies and consist of a wide variety of structural domains (see Fig. 1) (Lem-
mon and Schlessinger, 2010; Schlessinger, 2000a,b). RTKs within the same subfamily tend to have similar extracellular domains
and thus bind similar ligands. Therefore, each RTK subfamily has a family of ligand binding partners that are known to bind
some or all the members of that subfamily. These ligands bind to the receptors with varying affinities. Interestingly, there are
some RTKs that do not bind any of the currently known ligands. The identities of the ligand and the RTK in the complex determine
the nature of the signals that are transmitted into the cell (Karl et al., 2020; Trenker and Jura, 2020).
RTKs are classified by the presence of a catalytic kinase domain located on the IC region that is vital for activating downstream
signaling cascades that control cellular processes (Lemmon and Schlessinger, 2010; Nishimura et al., 2014; Schlessinger, 2000a,b).
Kinase activity requires ATP binding to a conserved active site of the kinase domain. Subsequently, ATP hydrolysis occurs resulting
in the transfer of a phosphate group from ATP to specific tyrosine residues. The first tyrosine that is phosphorylated is the one
located on the activation loop proximal to the active site. Then, through a process that is still not completely understood, other
tyrosine residues located on various intracellular domain sites also become phosphorylated. Many of the phosphorylated tyrosines
serve as docking sites for site-specific adaptor and effector proteins which initiate specific downstream signaling cascades (Lemmon
and Schlessinger, 2010; Del Piccolo and Hristova, 2017; Schlessinger, 2014). Within the same RTK subfamily, these phosphoryla-
tion sites tend to be highly conserved. In addition, RTKs in different subfamilies have different regulatory domains such as the jux-
tamembrane (JM) segment, post-kinase tail, and/or sterile alpha motif (SAM) domain which can harbor additional
phosphorylation sites (Lemmon and Schlessinger, 2010; Schlessinger, 2000a,b). As a result, the manner in which RTKs achieve
complete activation can be different for each RTK subfamily, and for each RTK as well.
RTK activity is controlled by the lateral interaction between RTKs on the cell surface, as it controls the proximity of the kinase
domains and thus the first step in the RTK activation process (Chen et al., 2020; Kavran et al., 2014; Paul and Hristova, 2019b;
Sarabipour and Hristova, 2016a,b; Singh et al., 2016). Therefore, RTK dimerization and oligomerization is vital for RTK signaling.
It has long been known that ligand binding stabilizes RTK dimers and thus it was considered that ligands are required for RTK
dimerization and oligomerization. However, now it is known that RTKs generally exist in monomer-dimer equilibrium in the
absence of ligand binding (Paul and Hristova, 2019b). Therefore, unliganded RTK dimers can exhibit basal levels of activity and
12 Receptor Tyrosine Kinases
Fig. 1 Architecture of the 20 RTK subfamilies.

can induce downstream signaling. In addition, most RTKs have been found to interact with other RTKs, either in the same family or
between subfamilies, and with other membrane proteins such as cadherins, integrins, and G-protein Coupled Receptors (GPCRs)
(Paul and Hristova, 2019a).
Each RTK and its activating ligands plays a specialized role in cellular signaling and thus all RTKs are critical for human devel-
opment and health. RTK signaling activates downstream signaling cascades including the Ras/MAPK, PLCg1/PKC, PI3K/Akt, and
STAT pathways, which are involved in a wide variety of cellular processes such as cell proliferation, differentiation, survival, and
migration (Chao et al., 2006; Lemmon and Schlessinger, 2010; Li and Hristova, 2006; Neben et al., 2019; Ornitz, 2000; Pasquale,
2010; Schlessinger and Lemmon, 2003; Schlessinger, 2000a,b, 2014; Smith et al., 2018; Sun and Bernards, 2014; Timsah et al.,
2014; Trenker and Jura, 2020). These signaling pathways are activated by binding and subsequent phosphorylation of specific cyto-
solic proteins such as Grb2, PLCg, NCK, FRS2, Shc, Jak, Gab1, SHP2, STAT, and the p85 subunit of PI3K, to name some notable
examples. Aberrant RTK activity and signaling has been implicated in many diseases and disorders including various cancers, neuro-
degenerative diseases, cardiovascular diseases, and developmental disorders (Boye et al., 2009; Browne et al., 2009; Cunningham
et al., 2007; Foldynova-Trantirkova et al., 2012; Nessa et al., 2009; Phay and Shah, 2010; Robertson et al., 2000; Vail et al., 2014;
Webster and Donoghue, 1997). RTK signaling abnormalities can arise in several ways: (i) overactivation or inhibited activation as
a result of mutations or deletions (including alternative splicing), (ii) overexpression due to gene amplification and (iii) the gener-
ation of oncogenic fusion proteins resulting from chromosomal translocation. Just about every RTK has been linked to disease.
Thus, in efforts to prevent or treat RTK-associated diseases, RTKs have become increasingly popular and promising drug targets (Sar-
aon et al., 2021). In this review, we discuss RTKs in pharmacological context, highlighting some of the RTK subfamilies and the
therapeutics that have been developed to target these receptors to combat disease.
RTK inhibitors target either the extracellular domain or the kinase domain, as the transmembrane domain is protected by the cell
membrane, and its role in RTK activation is still debated (Bocharov et al., 2017). Here we will begin by describing common archi-
tectural motifs of RTKs, as well as their function. Special emphasis will be placed on the structure of the kinase domain. This detailed
understanding of the domains will help with the understanding of how inhibitors work.
1.03.2 Architecture of RTK extracellular domains
The extracellular domains of the RTKs vary significantly between families as shown in Figs. 1 and 2, giving scientists opportunities to
design inhibitors that target specific RTK extracellular domains. Within a family, the extracellular domains share similar structures.
Some of the more common domains that are used as building blocks in many RTKs include immunoglobulin (Ig) domains, fibro-
nectin (FN) III domains, cysteine rich domains, and leucine rich domains. A common feature of RTKs is the significant degree of
conformational flexibility in the extracellular domains. The manner in which this occurs and the amount of conformational change
varies across the families, but in general RTKs must undergo some form of conformational change to bind the ligand and to engage
stabilizing inter-molecular contacts between the two EC domains in the RTK dimers. In fact, for some RTKs it has been observed that
different ligands can induce unique extracellular dimer conformations based solely on ligand identity (Freed et al., 2017; Plotnikov
et al., 2000).
Immunoglobulin (Ig) domains are one of the most prevalent domains in the human genome and are typically associated with
immune response (Travers et al., 2001). They are found in many RTKs, including FGFRs and VEGFRs. The immunoglobulin fold is
characterized by a pair of beta sheets linked by a single disulfide bond (Berg et al., 2002). The beta sheets are made up of anti-
parallel beta strands, and the fold is often described as a “sandwich-like” structure with the beta sheets on the outside and the hydro-
phobic residues in the interior. The Ig domains are capable of being strung together like “beads on a string” as their N and C termini
are at opposite ends of the structure (Bork et al., 1994). Many RTKs have a series of Ig domains, up to as many as seven in a row as in
the VEGFR subfamily. The Ig domain incorporates a series of loops close to the N-terminus that compose the highly variable
binding section. This can account for some of the variability in ligand binding across RTKs with Ig domains (Encyclopedia of Immu-
nology, 1999; Plotnikov et al., 2000). For example, FGFR1 and FGFR2 do not bind the same ligands with equal affinities, even
though they both possess three very similar Ig-like domains (Ornitz and Itoh, 2015). In addition, many proteins have ligand
binding domains that are in a cleft between two consecutive Ig domains. Immunoglobulin domains are also helpful in stabilizing
dimerization interactions as other structural features of the domain, such as the beta strands, can form favorable contacts with each
other (Berg et al., 2002).
Fibronectin III (FN3) domains are most commonly found in fibronectin, a protein important for wound healing (Campbell and
Spitzfaden, 1994; Leahy et al., 1992). FN3 domains are found in the Eph receptor family, the insulin receptor family, and the ROS1
family to name a few (Bencharit et al., 2007). They are similar to the Ig domains discussed above but sequence homology studies
suggest that they evolved independently (Buchanan and Revell, 2015). In fact, FN3 domains have such low sequence homology
amongst themselves that it is postulated that many families evolved this fold independently due to its versatility. FN3 domains
consist of two beta sheets that sandwich a hydrophobic core, but the sheets are not held together by a disulfide bridge as in the
Ig domains. The two beta sheets are made up of 4 and 3 strands respectively (Ward and Garrett, 2001). The main function of
the FN3 domain seems to be that it acts as a “spacer” to position other domains, and as a mediator of protein-protein interactions.
As in the Ig domains, the N and C-termini of the domain are at opposite ends, and thus FN3 domains can be strung one after the
other (Campbell and Spitzfaden, 1994).
Fig. 2 Ligand-bound RTK extracellular region structures. Shown are structures of the extracellular domains of EGFR, VEGFR1, FGFR1, EphA2, TrkA,
and IR. The gray rectangles indicate the cell membrane. EGFR: The complete structure of EGFR bound to EGF was assembled using PDB 1IVO (Ogiso
et al., 2002) and PDB 1YY9 (Li et al., 2005). Domains 1–3 (D1,D2,D3) and part of D4 are from 1IVO. D4 from 1YY9 was aligned to the partial D4
from 1IVO. VEGFR1: The structure of VEGFR1 bound to VEGF-A was assembled using PDB 5T89 (Markovic-Mueller et al., 2017) which consists of
domains 1–6 (Ig1–6) and VEGF-A. The Ig7 domain was obtained from a structure of the VEGFR2 domain 7 dimer (PDB 3KVQ (Yang et al., 2010))
and was aligned to PDB 5T89. FGFR1: The structure of FGFR1 bound to FGF2 was assembled from PDB 1FQ9 (Schlessinger, 2000a,b) which
includes domains Ig2–3 and the ligand FGF2 and PDB 2CKN (Kiselyov et al., 2006) which includes domain Ig1. The Ig1 domains were connected to
the Ig2 domains by an arbitrary linker. EphA2: The full structure of the EphA2 ectodomain bound to ephrin-A5 was assembled by aligning PDB 3MX0
(Himanen et al., 2010) with PDB 3FL7 (Himanen et al., 2010). 3MX0 consists of ephrin-A5 and all EphA2 domains except FN-III(2) while 3FL7
consists of all EphA2 domains but not the ligand. TrkA: The structure of TrkA bound to NGF (PDB 2IFG (Wehrman et al., 2007)). IR: The structure of
the insulin receptor bound to insulin (PDB 6SOF (Gutmann et al., 2020)).
Cysteine rich domains are found in a variety of proteins and are often associated with recognition and binding of Wnt, a protein
important for body axis patterning in embryogenesis (Abreu et al., 2002). They are found in the Trk, EGFR, and insulin receptor
subfamilies. Across the different proteins, cysteine rich domains perform many different functions (O’Leary et al., 2004). In the
case of EGFR, it is known that the cysteine rich domains are responsible for regulating the dimerization of EGFR via the creation
of an auto-inhibited extracellular conformation where the two domains are tethered together (Aertgeerts et al., 2011; Ferguson,
2008; Sihto et al., 2005). One of the cysteine rich domains in EGFR also contains the dimerization arm which is critical for
inter-protein interactions and determines the extracellular conformation of the dimer based on the identity of the bound ligand
(Freed et al., 2017). In the insulin receptor family, the cysteine rich domains interact with the ligand and help determine ligand
specificity via electrostatic interactions (Bork and Doolittle, 1992; Kavran et al., 2014; Scapin et al., 2017).
Leucine rich domains are found in EGFR, the insulin receptor and Trk family members. The 3D structure and consensus motif
of these RTK domains are remarkably similar to those found in leucine rich repeat proteins such as ankyrin, a family of proteins
that anchors membrane proteins to the cytoskeleton (Bork, 1993; Ng and Xavier, 2011; Zampieri and Chao, 2006). Leucine rich
repeats are known to form single-stranded right-handed b-helices. Leucine rich domains in RTKs have slightly more variable
sequences as compared to other leucine rich domains, and they sometimes have inserts in the consensus sequence which mani-
fest themselves as loops that do not affect the supercoiling of the chain (Ng and Xavier, 2011). In RTKs they are generally flanked
on at least one side by cysteine rich domains and they serve to mediate ligand binding as well as inter-protein interactions (Ward
and Garrett, 2001).
Here, we covered the most common extracellular domain motifs in the RTK sub-families that we discuss below, but this is by no
means an exhaustive list. Some other extracellular domains that appear in RTKs include the EGF-like domain, kringle domains, and
sushi domains (see Fig. 1). Some of these domains are well studied, and their function in RTKs is relatively clear, while others are
still waiting to be fully understood.
1.03.3 Overview of RTK kinase anatomy and function
On the intracellular side, RTKs contain a highly conserved kinase domain which is vital for RTK signaling. Here we discuss the
general architecture and function of the RTK kinase domains using FGFR1 as a model system. The biophysical adage states that
“function follows structure” and therefore it stands to reason that understanding the structure of a kinase and how it relates to
its function is critical for understanding and designing novel inhibitors.
RTK kinases are made up of two lobes, the N-lobe and the C-lobe connected via a hinge region (see Fig. 3). The N-lobe is
predominantly made up of beta sheets, with 1 alpha helix, known as the C-helix (shown in purple). The C-lobe is primarily
made up of alpha helices and turns. The C-lobe contains a hydrophobic alpha helix, termed the F-helix (shown in yellow in
Fig. 3), which is buried and is responsible for providing the kinase with much of its structure.
Researchers have used local spatial patterning alignment to determine that certain physical locations in the kinase have
conserved residues, even though there is no sequence homology of note near these regions (Kornev and Taylor, 2010). These
conserved, non-contiguous residues make up two (relatively) linear structures in the interior of the kinase that are called “hydro-
phobic spines” (Fig. 3). The F-helix contributes the bases of both the regulatory (R) spine (shown in red in Fig. 3) and the catalytic
(C) spine (shown in orange). These spines provide stabilizing hydrophobic contacts between the N and C lobe, helping the kinase
form its canonical “kidney bean” shape (Kornev and Taylor, 2010; McClendon et al., 2014). The attachment of the spines to the F-
helix keeps all elements anchored together and ensures that the kinase adopts its active structure (Fig. 3). These spines assemble and
disassemble based on the local biochemistry of the kinase, meaning that these spines can form and then disassemble as the kinase
lapses into an inactive state.
The regulatory spine is essential for catalytic activity, as it has been shown that manipulation of residues in the regulatory spine
from hydrophobic to hydrophilic would decrease or completely abolish catalytic activity (Meharena et al., 2013; Robinson, 2013).
The catalytic spine is critical for the positioning of the ATP and the substrates, and also provides key catalytic machinery for kinase
function (Kornev and Taylor, 2010). The adenine in ATP completes the catalytic spine (see the break in the C-spine in Fig. 3) and
therefore the catalytic spine is unable to form in the absence of ATP or an ATP analog.
Fig. 3 RTK kinase domain structures. Shown are structures for the kinase domains of FGFR1, EGFR, VEGFR2, EphA2, TrkB, and IR. The FGFR1
kinase domain (top) is used as an example to highlight the various motifs. All elements are colored similarly: gatekeeper residue (magenta), KEN
triad (gray), hinge (light green), F-helix (yellow), C-helix (purple), DFG motif (salmon), HRD motif (dark green), activation loop tyrosine residues
(cyan), APE motif (black), C-spine (orange), R-spine (red). Structures are from (Bae et al., 2010; Bertrand et al., 2012; Heinzlmeir et al., 2016;
Hubbard et al., 1994; McTigue et al., 1999; Zhang et al., 2006).
The activation segment is a section of the kinase that includes the activation loop and the DFG motif discussed below. This
segment provides stability to the C-lobe and varies the most between kinases in terms of length and sequence. The activation
loop is relatively unstructured when inactive and can block substrates from binding to the kinase. Upon activation, the activation
loop assumes its open conformation and allows substrates to bind to the C-lobe (McClendon et al., 2014; Taylor and Kornev,
2011). The activation loop contains a tyrosine residue (sometimes more than one), known as the activation site(s) that needs to
be phosphorylated for the kinase to become active. The main activation site on FGFR1 is residues Y653/Y654. Upon phosphory-
lation, the phospho-tyrosine forms hydrogen bonds with both the N and C-lobe, thus forming the final critical contacts to stabilize
the active kinase conformation. Once the kinase is active and both spines are fully formed, the conformation can “breathe” to allow
ATP and substrates into the active site.
The catalytic loop is a loop in the C-lobe that contains the HRD motif. The HRD motif, residues 621–623 in FGFR1, contains the
catalytic base, D623 in FGFR1, which is a key catalytic residue (Farrell and Breeze, 2018). The catalytic base is often a conserved
aspartic acid that is critical for preparing the tyrosine being phosphorylated for the phosphate transfer. The histidine in the HRD
motif helps make up the regulatory spine, while the backbone of the arginine anchors the HRD to the F helix to help stabilize
the active conformation of the kinase (McClendon et al., 2014; La Sala et al., 2016).
The DFG motif in the activation segment is positioned at the N-terminus of the activation loop. Depending on the phosphor-
ylation state of the activation site, the DFG motif can adopt either an “in” conformation in active kinases, which allows for the regu-
latory spine to form, or an “out” conformation, classically associated with an inactive kinase. The difference between these two
conformations is a rotation of the phenylalanine of almost 180 degrees (Fig. 4) (Treiber and Shah, 2013). The DFG motif is critical
for positioning of magnesium ions (Mg2þ) present in the active site, needed to overcome the net negative charge of the phosphates
in the ATP tail. When the DFG motif adopts the “in” conformation, the phenylalanine binds to the histidine side chain from the
HRD motif, stabilizing the active conformation (McClendon et al., 2014).
Another critical feature of the kinase is the gatekeeper residue, in FGFR1 this is V561. The gatekeeper residue is generally a small
hydrophobic residue that helps determine the size of the hydrophobic pocket that forms when the kinase is inactive and thus the
DFG motif is in the “out” conformation. This pocket is often targeted by inhibitors as a way to stabilize the DFG-out motif and keep
the kinase inactive (Treiber and Shah, 2013). Mutations in this gatekeeper residue can confer drug resistance via steric hindrance, by
either disrupting hydrogen bonding or by stabilizing the DFG-in conformation. As the gatekeeper residue is often small, a mutation
to a large and/or charged residue can prevent inhibitors from entering the binding pocket. A common mutation is from valine to
methionine, which not only confers steric inhibition, but alters the hydrophobicity of the pocket as well (Sohl et al., 2015).
The glycine rich loop is a flexible linker in the N-lobe. This loop has the motif of GxGxVG where the Gs are conserved glycines,
the x’s are random residues, and the V is a hydrophobic residue. In FGFR1, residues 485–490 represent the glycine rich loop which
is important for aligning the phosphate tail of the ATP molecule in the active site (Matte et al., 1998).
Fig. 4 FGFR1 kinase domain structures in the DFG-in or DFG-out conformation. (A) The FGFR1 kinase domain in complex with the ATP analog
AMP-PCP shows the DFG motif in the “in” conformation. On the left is the entire kinase domain structure and on the right is a zoomed-in view of the
binding site. (B) Inhibitors such as ponatinib cause a structural rearrangement of the DFG motif to the “out” conformation. (C) Inhibitors such as
AZD4547 stabilize the “DFG-in” conformation. Structures are from (Bae et al., 2009; Tucker et al., 2014).
The C-helix in the N-lobe is critical for activation. It can swing outwards from the active site, disrupting contacts between the N
and C-lobes and disabling the catalytic domain from performing nucleophilic attack and thus attaching a phosphate group to the
tyrosine. A KEN triad of residues, N546, E562, and K638 in FGFR1, forms at least 10 observable polar bonds in the inactive kinase
and makes up what is known as the molecular brake, which stabilizes the inactive conformation (Klein et al., 2015). Upon activa-
tion, the glutamate undergoes significant conformational change, and the lysine moves slightly, reducing the number of polar
bonds formed to three and allowing the C-helix to swing in towards the active site. Notably, not all RTK sub-families have this
KEN triad (Farrell and Breeze, 2018; McClendon et al., 2014).
1.03.4 ATP binding and the act of phosphorylation
The ATP is positioned very precisely within the kinase domain (see Fig. 4) and many of the kinase motifs discussed above play a role
in the alignment, binding, and cleavage of the ATP. First, the adenine base fits into a hydrophobic pocket between the N and C-lobes
of the kinase and completes the catalytic spine. The adenine base then forms multiple hydrogen bonds with residues in the hinge
region (Beenstock et al., 2016). The phosphate tail of the ATP is the most critical component for positioning and catalysis as the
proper alignment is what will allow the enzyme to transfer the g phosphate (the phosphate on the end) to the substrate tyrosine.
Next in the alignment ballet, the DFG motif adopts an “in” conformation where the asparagine can bind a Mg2þ ion, while a second
asparagine in the catalytic loop binds to a second Mg2þ ion. The charge of the magnesium ions serves to stabilize the negatively
charged tail of the ATP. In addition, the magnesium ions recruit water molecules into the pocket, which help to anchor the ATP
to the kinase and also create a “coordination sphere” to accommodate the phosphoryl transfer onto the tyrosine residue (Matte et al.,
1998; McClendon et al., 2014). At least one water molecule is necessary for the hydrolysis of ATP. The glycine rich loop interacts
with the b and g phosphates, further stabilizing the tail. At last, a conserved lysine in the C-helix (K514) further serves to coordinate
the locations of the b and g phosphates. To recap, the ATP is now forming stabilizing contacts with the hinge region, the C-helix, the
glycine rich loop in the N-lobe, and the catalytic loop in the C-lobe (Matte et al., 1998).
The catalytic base binds to the P þ 1 site of the substrate (or the amino acid immediately following the tyrosine to be phosphor-
ylated) and the substrate is further stabilized via additional contacts with the C-lobe as well as through coordination with the
magnesium ions (McClendon et al., 2014; Taylor and Kornev, 2011).
The act of phosphorylation is not completely understood but involves the magnesium ions increasing the modulation of the
charges of the b and g phosphates of ATP to increase their mutual repulsion. Then, the catalytic base abstracts a proton from
the tyrosine substrate, which then allows the tyrosine to perform nucleophilic attack on the g phosphate from the ATP (Matte
et al., 1998). This causes cleavage of the g phosphate of ATP and the phosphoryl group is transferred to the tyrosine to create a phos-
pho-tyrosine (Fig. 5).
1.03.4.1 Post-Kinase domains

While most RTKs have a short stretch of amino acids immediately following the C-terminus of the kinase, some RTKs have addi-
tional domains following the kinase that may play a role in kinase function. Examples include sterile alpha motif (SAM) domains,
PDZ binding motifs, and long post-kinase tails.
Fig. 5 Schematic of ATP hydrolysis and tyrosine phosphorylation. The tyrosine performs nucleophilic attack on the g phosphate of ATP
(highlighted in green) which results in the transfer of a phosphoryl group onto the tyrosine to create phospho-tyrosine and ADP as a byproduct.
SAM domains are found in many different proteins and are often associated with mediating protein-protein interactions, but
actually have a large array of functions (Kim and Bowie, 2003). They can bind to both other SAM domains and non-SAM domains
(Singh et al., 2017). They are predominantly alpha helical in structure and are capable of forming higher order oligomers in solution
(Stapleton et al., 1999). SAM domains are found in the Eph receptor subfamily.
Also found in the Eph receptor subfamily are PDZ binding motifs which are located on the C-terminal ends of these receptors.
PDZ binding motifs are three amino acids in length and bind PDZ domains of proteins. These domains are named after the three
proteins that were first discovered to share the domain: PSD95, Dlg1, and zo-1 (Lee and Zheng, 2010).
Finally, the most common “domain” following the kinase domain is the long post-kinase tail. These tails perform a number of
functions: they may possess additional phosphorylation sites, they can bind to downstream signaling partners, or they can act as
regulatory sequences. While the kinase domains are homologous across the entire RTK family, and the extracellular domains are
homologous across sub-families, there is little sequence homology between the post-kinase tails (Crudden and Girnita, 2020).
These tails tend to be unstructured and are not well understood.
1.03.4.2 Overview of ligands

RTK ligands, often called growth factors, tend to be small in size, they range from 5 kDa to 50 kDa (Ogiso et al., 2002; Toth et al.,
2001; Weiss et al., 2000; Wlesmann et al., 1999). Structures of some ligands that bind RTKs are shown in Fig. 6 and the ligand
binding sites are shown in Fig. 2. There are paracrine ligands, which are secreted and activate receptors in a small, localized
area, as well as endocrine ligands that are expressed in one tissue but travel through the bloodstream to activate cells elsewhere
in the body (Beenken and Mohammadi, 2009). In some special cases such as the ephrins, the ligands are produced in a neighboring
cell and remain tethered to that cell via anchors in the plasma membrane (Darling and Lamb, 2019; Toth et al., 2001). Some ligands
are actually trafficked in vesicles and endocytosed into the cells for use (Chao, 2003; Maness et al., 1994; Wilding et al., 2020).
Until recently, it was believed that each RTK sub-family has its own specific set of growth factors that bind and activate the recep-
tors. Now it is known that some ligands are very specific and only bind to one RTK while others are more promiscuous and bind to
multiple RTKs. Sometimes, cross-family activation has been seen which means that ligands bind to more than one RTK subfamily
(Paul and Hristova, 2019a).
Ligands are either monomeric or dimeric (although some in vitro assays have shown evidence of higher order oligomers), which
affects how they can bind to and interact with the RTK dimer (Lu et al., 2001; Weiss et al., 2000). A monomeric ligand can bind to
the dimer in a 2:2 ratio, meaning 2 ligands bind to a dimer containing two receptors. A dimeric ligand can bind in a 1:2 ratio
meaning that 1 ligand dimer binds to the two receptors in a dimer. This may seem like a small difference, but simulations show
significant differences in RTK dimerization and behavior in response to monomeric and dimeric ligands (Paul and Hristova,
2019b).
In summary, some ligands across subfamilies are similar and potentially evolutionarily linked, while some like the ephrins are
unique. Ultimately, the purpose of each of the ligands is the same, to bind to the extracellular domain of the RTKs, to stabilize the
dimers, and to induce allosteric conformational changes that will ensure full activity of the kinases. The close proximity of the
kinases, and their correct orientation with respect to each other in the dimers allows them to auto-phosphorylate each other and
become catalytically active (Li and Hristova, 2006; Paul and Hristova, 2019b).
Fig. 6 Structures of ligands that bind the EGFR, VEGFR, FGFR, Eph, Trk, and IR families. EGF, FGF2, ephrin-A5, and insulin are monomeric ligands
while VEGF-A and NGF are dimeric ligands. Structures are from (Gutmann et al., 2020; Himanen et al., 2010; Markovic-Mueller et al., 2017; Ogiso
et al., 2002; Schlessinger, 2000a,b; Wehrman et al., 2007).
Fig. 7 Illustration of some common RTK inhibition strategies. Ligand traps (top) are inhibitors that bind to the ligand and prevent its binding to the
receptor. RTK inhibitors that target the receptor to block ligand binding (left) can be one of two types: (i) allosteric inhibitors that cause structural
changes to prevent ligand binding, or (ii) orthosteric inhibitors that directly block ligand binding. Other inhibitors do not interfere with ligand binding
but inhibit receptor dimerization (bottom). Tyrosine kinase inhibitors (TKIs, right) are small molecules that bind specifically to the kinase domain and
alter the kinase activity.
There have been great successes in the large-scale production of synthetic RTK ligands. Some of them are being used as drugs.
One of the most common examples is porcine insulin to treat diabetes. Porcine insulin is very similar to human insulin, and could
be expressed and purified, until recently, much more easily than human insulin (Weiss et al., 2000). Synthetic ligands are also used
in research; one example is a soluble ephrin variant that allows for easier bio-activity studies in vitro (Darling and Lamb, 2019).
1.03.5 Types of Inhibitors and how they work
Fig. 7 show some common inhibition strategies that we will discuss here. They include (i) inhibition of ligand binding (using either
ligand traps (top) or allosteric/orthosteric binding inhibitors (left)), (ii) inhibition of RTK dimerization (bottom), or (iii) inhibition
of kinase function (right).
To prevent ligand binding and thus disable the ligand, a signaling incompetent molecule can be used to bind to the receptor and
either allosterically prevent ligand binding or outcompete the ligand for the binding site. Alternatively, the ligand can be disabled by
using drugs to sequester the ligand, and thus prevent it from binding to the receptor (Katoh, 2016, 2019; Tanner and Grose, 2016).
To prevent dimerization, antibodies or other large molecules are used to bind the receptor and sterically hinder dimerization
(Katoh, 2016; Tanner and Grose, 2016). The most common method to inhibit kinase function is to use a small molecule called
tyrosine kinase inhibitor (TKI), which binds to the kinase and prevents it from functioning properly.
1.03.5.1 TKIs
Small molecule inhibitors generally refer to the class of inhibitors known as tyrosine kinase inhibitors or TKIs. TKIs work by binding
to the kinase domain and either blocking the ATP binding site, or allosterically preventing ATP hydrolysis (Katoh, 2016). To date,
the TKIs that bind to the active site contain a pyrimidine or pyrimidine analog at their core (Liu and Gray, 2006; Milik et al., 2017).
Small molecule inhibitors come in a wide array of specificities. Some TKIs bind to the kinase domains of many families of RTKs,
some bind only to RTKs within the same family, some bind to a subset of RTKs within a family, and some only bind to a specific RTK
or RTK mutant. TKIs are the most commonly used inhibitors in cancer treatment that target the RTKs (Katoh, 2016; Tanner and
Grose, 2016). Inhibitors that target mutant pathogenic variants of RTKs are widely studied due to their potential utility as anti-
cancer drugs (Ko et al., 2021; Tanner and Grose, 2016; Touat et al., 2015; Yue et al., 2021).
Fig. 8 Structures of tyrosine kinase inhibitors (TKIs) from different classes. Class 1: gefitinib, Class 2: ponatinib, Class 1.5: AZD4547, Class 3:
trametinib, Class 4: SSR128129E, Class 5: neratinib, Class 6: futibatinib (TAS-120). The pyrimidine or pyrimidine analog groups are highlighted in
red, the hydrophilic, solubilizing groups are highlighted in blue, and the hydrophobic groups are highlighted in yellow.
There are seven classes of tyrosine kinase inhibitors (Engelhardt et al., 2019; Gower et al., 2014; Hartmann et al., 2009; Liu and
Gray, 2006; Park et al., 2012; Roskoski, 2020; Yosaatmadja et al., 2015). Class 1 TKIs bind to the active, DFG-in, C-helix in confor-
mation. Class 2 bind to the inactive, DFG-out, C-helix out conformation. Class 1.5 bind the conformation mid-way between active
and inactive, where the DFG is in but the C-helix is out (Park et al., 2012). Classes 3 and 4 are non-ATP competitive inhibitors that
prevent catalytic activity through allosteric effects. Class 5 pertains to bivalent inhibition in which the inhibitor targets two distinct
binding surfaces of the kinase domain (Gower et al., 2014) and class 6 refers to irreversible inhibition, often through the formation
of covalent bonds (Roskoski, 2020; Yosaatmadja et al., 2015). Examples of inhibitors in each class is shown in Fig. 8. The scaffold
region in Fig. 8 is highlighted in red; notice how all the inhibitors contain a pyrimidine or pyrimidine analog. The hydrophilic
region which is responsible for modulating the solubility of the TKI is shown in blue. The hydrophobic region which modulates
selectivity and potency is shown in yellow (Engelhardt et al., 2019; Liu and Gray, 2006).
Inhibitors of classes 1, 2, and 1.5 are the most common. These inhibitors tend to include a core scaffold (red in Fig. 8) that serves
as an adenine mimetic and binds to the hinge region (Yun et al., 2007). Class 2 TKIs are increasingly becoming more common due
to the ability to fine tune their selectivity and potency. This can be done by taking advantage of the DFG-out motif and utilizing the
hydrophobic pocket that forms when the phenylalanine flips out. The selectivity of a class 2 TKI can be adjusted by changing the
group that extends into this pocket (known as the “back pocket”). In fact, in order to balance the potency of such inhibitors, phar-
macologists generally add a solubilizing group to the end of the inhibitor (yellow in Fig. 8) that extends into the solvent (Ishikawa
et al., 2011; Milik et al., 2017). This adds an interesting push/pull effect as the hydrophobic group wants to nest into the back pocket
and stay there, and the solubilizing group is hydrophilic and wants to be in solvent so it works to pull the inhibitor back into
solution.
Finally, we note that there are some small molecule inhibitors that do not bind to the catalytic domain, but rather bind to the
extracellular domain and inhibit signaling by preventing ligand binding and thus dimerization and kinase activation in much the
same way as some of the antibodies discussed below (Aertgeerts et al., 2011; Noberini et al., 2008).
1.03.5.2 Antibodies
Antibodies are large proteins ( 150 kDa) that can bind to a variety of substrates with high specificity. Antibodies generally work by
binding to the extracellular domain of the RTK and either by preventing dimerization via steric hindrance or by preventing the
ligand from binding (Katoh, 2016). Once the antibodies identify a target, they bind strongly to it (dissociation constants in the
sub-nM and nM range). The general structure of an antibody looks a bit like a Y as shown in Fig. 9. This Y is composed of two major
regions, the variable region and the constant region (Chiu et al., 2019). The variable region is the region that has low sequence
homology and adapts to identify and bind to different substrates (or antigens). As seen in Fig. 9, the variable antigen binding region
resembles a notched groove, which optimizes the exposed surface area that the antibody can use to bind to its substrate. The variable
region is often called the Fragment antigen binding domain, or Fab (Chiu et al., 2019).
The specificity of antibodies is often modulated via electrostatic, rather than hydrophobic, interactions, such that the selec-
tivity of the antibody for the antigen can be tuned (Travers et al., 2001). The antibody-substrate interaction can take on many
forms, but it is generally accepted that upon binding both the antibody and the substrate undergo localized conformational
changes. These changes can be sorted into three different categories: Lock and key, induced fit, and conformational selection.
Lock and key allows the two proteins to fit together without requiring large conformational changes, much like a key fitting
into a lock. Induced fit is the most dynamic method of binding, and is sometimes attributed to the antibodies with the highest
antigen diversity, as both the antibody and the antigen undergo major conformational changes to fit together. This conforma-
tional flexibility allows antibodies to vary in their ability to recognize both the charges and the shape of the antigen. Finally,
the conformational selection method allows the variable region of the antibody to sample many different conformations in
solution so it can bind when it finds an antigen that it fits, both sterically and electrostatically. This is quite useful as it
allows the antibody to bind to an antigen that may have undergone minor modifications due to its local microenvironment
(Chiu et al., 2019).
The constant region has low sequence variability and is historically known to crystallize easily. It is thus called the Fc domain for
“fragment crystallizable” (Chiu et al., 2019). This region is used to classify antibodies into different classes of immunoglobulins:
IgM, IgD, IgG, IgA, and IgF based on their constant regions. IgG is the most common type of antibody found in the blood. It is
generally used as the starting point for antibody design and is the type referred to in this article.
Fig. 9 Structure of a monoclonal immunoglobulin antibody (PDB 1IGT). The heavy chains are labeled and colored red and blue, the light chains are
labeled and colored orange and cyan, and the disulfide bonds are shown as pairs of spheres and are circled. Structure is from (Harris et al., 1997).
Fig. 10 Structure of an RNA aptamer bound to IgG domains (PDB 3AGV). Structure is from (Nomura et al., 2010).
The really great thing about anti-RTK antibodies is their diversity in mechanisms of action and targets. Some antibodies have
been designed to target the RTK by binding to the extracellular domain. This can either target the cell for destruction, as it may
initiate an immune response, or it can prevent ligand binding or dimerization via steric occlusion (Bennasroune et al., 2004; Leo-
pold and Verkhusha, 2020; Linardic and Crose, 2011; Yamaoka et al., 2018). The other way that antibodies have been used as RTK
inhibitors is by designing antibodies that target the ligand. By binding to the ligand, the antibodies mark it for degradation and
prevent it from binding to the RTK, thus preventing the perpetuation of signaling (Bennasroune et al., 2004; Leopold and Verkhu-
sha, 2020; Linardic and Crose, 2011; Yamaoka et al., 2018).
1.03.5.3 Aptamers
RNA and DNA aptamers, as shown in Fig. 10, are short nucleotide sequences that behave very much like antibodies. They are single
stranded but can fold into complex geometries. They are generally selected from a large random sequence pool and can display high
selectivity and potency (Blind and Blank, 2015; Lakhin et al., 2013). Aptamers can be advantageous over antibodies because they
can be produced synthetically, often at a much lower cost than an antibody, and can have more conducive storage requirements.
Aptamers also have the advantage of being modifiable to prevent degradation in vivo and during storage. Thus, they may be
effective in lower quantities than antibodies. Unmodified aptamers are cleared from the bloodstream in a matter of minutes or
hours, while modified aptamers can last for days or weeks (Lakhin et al., 2013). DNA aptamers seem to have a slightly higher
intrinsic stability than RNA aptamers, but there has yet been no clear advantage identified for one type over another (Lakhin
et al., 2013).
Aptamers often need to be conjugated with polyethylene glycol to increase their mass. These short nucleotide sequences are
generally less than 15 kDa and can be cleared by the kidneys. Increasing the mass to 20–40 kDa can help solve this problem (Lakhin
et al., 2013). Probably the biggest drawback to the use of aptamers is the time and labor required to design, select, and test the
aptamers. In addition, the quality of the aptamer is often dependent on the selection protocol used, and therefore a sub-
optimal protocol can result in aptamers with low affinity or selectivity (Blind and Blank, 2015). Finally, even the most selective
aptamer can exhibit some cross-reactivity and can interact with similar receptors. This means that, for example, an aptamer that
targets FGF2, a ligand for the FGFR family, may also bind to EGF, a ligand for the ErbB family, and thus result in off-target effects
(Blind and Blank, 2015).
1.03.6 Ligand traps
Ligand traps work by binding to the ligand and preventing it from binding to the receptor or they can bind both the ligand and the
extracellular domain of the signaling-capable receptor. This serves double duty, because not only does it sequester the ligand, it also
prevents the receptor from dimerizing and thus becoming active (Chiu et al., 2019; Wang et al., 2012).
Ligand traps can take on many forms such as RNA/DNA aptamers or truncated versions of the extracellular domain of the recep-
tors. Truncated extracellular domains are soluble versions of the receptor that bind the ligand and essentially compete with the full-
length receptor for the ligands on the cell surface. Truncated extracellular domains resemble some version of the ligand’s cognate
receptor or a receptor from the same family. This often includes just a short truncation of the extracellular domain and will include
the ligand binding domain and any domains necessary for binding. These soluble receptors have no signaling capabilities, so they
render the ligand ineffective (Adams et al., 2009).
RNA and DNA aptamers can work in a similar manner, by binding the ligand and preventing it from binding to the receptor
(Esposito et al., 2011). Finally, the last kind of ligand trap is an anti-ligand antibody. These antibodies are raised against specific
ligands and sequester them to prevent them from activating the receptor. An antibody functioning as a ligand trap has the same
structure as the antibodies discussed above, with a variable chain that targets the ligand instead of the receptor.
Another random document with
no related content on Scribd:
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright law in
the United States and you are located in the United States, we do
not claim a right to prevent you from copying, distributing,
performing, displaying or creating derivative works based on the
work as long as all references to Project Gutenberg are removed. Of
course, we hope that you will support the Project Gutenberg™
mission of promoting free access to electronic works by freely
sharing Project Gutenberg™ works in compliance with the terms of
this agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms of
this agreement by keeping this work in the same format with its
attached full Project Gutenberg™ License when you share it without
charge with others.
1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside the
United States, check the laws of your country in addition to the terms
of this agreement before downloading, copying, displaying,
performing, distributing or creating derivative works based on this
work or any other Project Gutenberg™ work. The Foundation makes
no representations concerning the copyright status of any work in
any country other than the United States.
1.E. Unless you have removed all references to Project Gutenberg:
1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project Gutenberg™
work (any work on which the phrase “Project Gutenberg” appears, or
with which the phrase “Project Gutenberg” is associated) is
accessed, displayed, performed, viewed, copied or distributed:
This eBook is for the use of anyone anywhere in the United
States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it away
or re-use it under the terms of the Project Gutenberg License
included with this eBook or online at www.gutenberg.org. If you
are not located in the United States, you will have to check the
laws of the country where you are located before using this
eBook.
1.E.2. If an individual Project Gutenberg™ electronic work is derived

from texts not protected by U.S. copyright law (does not contain a
notice indicating that it is posted with permission of the copyright
holder), the work can be copied and distributed to anyone in the
United States without paying any fees or charges. If you are
redistributing or providing access to a work with the phrase “Project
Gutenberg” associated with or appearing on the work, you must
comply either with the requirements of paragraphs 1.E.1 through
1.E.7 or obtain permission for the use of the work and the Project
Gutenberg™ trademark as set forth in paragraphs 1.E.8 or 1.E.9.
1.E.3. If an individual Project Gutenberg™ electronic work is posted

with the permission of the copyright holder, your use and distribution
must comply with both paragraphs 1.E.1 through 1.E.7 and any
additional terms imposed by the copyright holder. Additional terms
will be linked to the Project Gutenberg™ License for all works posted
with the permission of the copyright holder found at the beginning of
this work.
1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files containing a
part of this work or any other work associated with Project
Gutenberg™.
1.E.5. Do not copy, display, perform, distribute or redistribute this

electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1 with
active links or immediate access to the full terms of the Project
Gutenberg™ License.
1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if you
provide access to or distribute copies of a Project Gutenberg™ work
in a format other than “Plain Vanilla ASCII” or other format used in
the official version posted on the official Project Gutenberg™ website
(www.gutenberg.org), you must, at no additional cost, fee or expense
to the user, provide a copy, a means of exporting a copy, or a means
of obtaining a copy upon request, of the work in its original “Plain
Vanilla ASCII” or other form. Any alternate format must include the
full Project Gutenberg™ License as specified in paragraph 1.E.1.
1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™ works
unless you comply with paragraph 1.E.8 or 1.E.9.
1.E.8. You may charge a reasonable fee for copies of or providing

access to or distributing Project Gutenberg™ electronic works
provided that:
• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
Foundation at the address specified in Section 4, “Information
about donations to the Project Gutenberg Literary Archive
Foundation.”
• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.
• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.
• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.
1.E.9. If you wish to charge a fee or distribute a Project Gutenberg™

electronic work or group of works on different terms than are set
forth in this agreement, you must obtain permission in writing from
the Project Gutenberg Literary Archive Foundation, the manager of
the Project Gutenberg™ trademark. Contact the Foundation as set
forth in Section 3 below.
1.F.
1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on, transcribe
and proofread works not protected by U.S. copyright law in creating
the Project Gutenberg™ collection. Despite these efforts, Project
Gutenberg™ electronic works, and the medium on which they may
be stored, may contain “Defects,” such as, but not limited to,
incomplete, inaccurate or corrupt data, transcription errors, a
copyright or other intellectual property infringement, a defective or
damaged disk or other medium, a computer virus, or computer
codes that damage or cannot be read by your equipment.
1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except

for the “Right of Replacement or Refund” described in paragraph
1.F.3, the Project Gutenberg Literary Archive Foundation, the owner
of the Project Gutenberg™ trademark, and any other party
distributing a Project Gutenberg™ electronic work under this
agreement, disclaim all liability to you for damages, costs and
expenses, including legal fees. YOU AGREE THAT YOU HAVE NO
REMEDIES FOR NEGLIGENCE, STRICT LIABILITY, BREACH OF
WARRANTY OR BREACH OF CONTRACT EXCEPT THOSE
PROVIDED IN PARAGRAPH 1.F.3. YOU AGREE THAT THE
FOUNDATION, THE TRADEMARK OWNER, AND ANY
DISTRIBUTOR UNDER THIS AGREEMENT WILL NOT BE LIABLE
TO YOU FOR ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL,
PUNITIVE OR INCIDENTAL DAMAGES EVEN IF YOU GIVE
NOTICE OF THE POSSIBILITY OF SUCH DAMAGE.
1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you

discover a defect in this electronic work within 90 days of receiving it,
you can receive a refund of the money (if any) you paid for it by
sending a written explanation to the person you received the work
from. If you received the work on a physical medium, you must
return the medium with your written explanation. The person or entity
that provided you with the defective work may elect to provide a
replacement copy in lieu of a refund. If you received the work
electronically, the person or entity providing it to you may choose to
give you a second opportunity to receive the work electronically in
lieu of a refund. If the second copy is also defective, you may
demand a refund in writing without further opportunities to fix the
problem.
1.F.4. Except for the limited right of replacement or refund set forth in
paragraph 1.F.3, this work is provided to you ‘AS-IS’, WITH NO
OTHER WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED,
INCLUDING BUT NOT LIMITED TO WARRANTIES OF
MERCHANTABILITY OR FITNESS FOR ANY PURPOSE.
1.F.5. Some states do not allow disclaimers of certain implied

warranties or the exclusion or limitation of certain types of damages.
If any disclaimer or limitation set forth in this agreement violates the
law of the state applicable to this agreement, the agreement shall be
interpreted to make the maximum disclaimer or limitation permitted
by the applicable state law. The invalidity or unenforceability of any
provision of this agreement shall not void the remaining provisions.
1.F.6. INDEMNITY - You agree to indemnify and hold the

Foundation, the trademark owner, any agent or employee of the
Foundation, anyone providing copies of Project Gutenberg™
electronic works in accordance with this agreement, and any
volunteers associated with the production, promotion and distribution
of Project Gutenberg™ electronic works, harmless from all liability,
costs and expenses, including legal fees, that arise directly or
indirectly from any of the following which you do or cause to occur:
(a) distribution of this or any Project Gutenberg™ work, (b)
alteration, modification, or additions or deletions to any Project
Gutenberg™ work, and (c) any Defect you cause.
Section 2. Information about the Mission of

Project Gutenberg™
Project Gutenberg™ is synonymous with the free distribution of
electronic works in formats readable by the widest variety of
computers including obsolete, old, middle-aged and new computers.
It exists because of the efforts of hundreds of volunteers and
donations from people in all walks of life.
Volunteers and financial support to provide volunteers with the

assistance they need are critical to reaching Project Gutenberg™’s
goals and ensuring that the Project Gutenberg™ collection will
remain freely available for generations to come. In 2001, the Project
Gutenberg Literary Archive Foundation was created to provide a
secure and permanent future for Project Gutenberg™ and future
generations. To learn more about the Project Gutenberg Literary
Archive Foundation and how your efforts and donations can help,
see Sections 3 and 4 and the Foundation information page at
www.gutenberg.org.
Section 3. Information about the Project
Gutenberg Literary Archive Foundation
The Project Gutenberg Literary Archive Foundation is a non-profit
501(c)(3) educational corporation organized under the laws of the
state of Mississippi and granted tax exempt status by the Internal
Revenue Service. The Foundation’s EIN or federal tax identification
number is 64-6221541. Contributions to the Project Gutenberg
Literary Archive Foundation are tax deductible to the full extent
permitted by U.S. federal laws and your state’s laws.
The Foundation’s business office is located at 809 North 1500 West,

Salt Lake City, UT 84116, (801) 596-1887. Email contact links and up
to date contact information can be found at the Foundation’s website
and official page at www.gutenberg.org/contact
Section 4. Information about Donations to

the Project Gutenberg Literary Archive
Foundation
Project Gutenberg™ depends upon and cannot survive without
widespread public support and donations to carry out its mission of
increasing the number of public domain and licensed works that can
be freely distributed in machine-readable form accessible by the
widest array of equipment including outdated equipment. Many small
donations ($1 to $5,000) are particularly important to maintaining tax
exempt status with the IRS.
The Foundation is committed to complying with the laws regulating

charities and charitable donations in all 50 states of the United
States. Compliance requirements are not uniform and it takes a
considerable effort, much paperwork and many fees to meet and
keep up with these requirements. We do not solicit donations in
locations where we have not received written confirmation of
compliance. To SEND DONATIONS or determine the status of
compliance for any particular state visit www.gutenberg.org/donate.
While we cannot and do not solicit contributions from states where

we have not met the solicitation requirements, we know of no
prohibition against accepting unsolicited donations from donors in
such states who approach us with offers to donate.
International donations are gratefully accepted, but we cannot make

any statements concerning tax treatment of donations received from
outside the United States. U.S. laws alone swamp our small staff.
Please check the Project Gutenberg web pages for current donation
methods and addresses. Donations are accepted in a number of
other ways including checks, online payments and credit card
donations. To donate, please visit: www.gutenberg.org/donate.
Section 5. General Information About Project

Gutenberg™ electronic works
Professor Michael S. Hart was the originator of the Project
Gutenberg™ concept of a library of electronic works that could be
freely shared with anyone. For forty years, he produced and
distributed Project Gutenberg™ eBooks with only a loose network of
volunteer support.
Project Gutenberg™ eBooks are often created from several printed

editions, all of which are confirmed as not protected by copyright in
the U.S. unless a copyright notice is included. Thus, we do not
necessarily keep eBooks in compliance with any particular paper
edition.
Most people start at our website which has the main PG search
facility: www.gutenberg.org.
This website includes information about Project Gutenberg™,

including how to make donations to the Project Gutenberg Literary
Archive Foundation, how to help produce our new eBooks, and how
to subscribe to our email newsletter to hear about new eBooks.

Ebook Comprehensive Pharmacology 7 Volume Set PDF Full Chapter PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Ebook Comprehensive Pharmacology 7 Volume Set PDF Full Chapter PDF

Uploaded by

Copyright:

Available Formats

Comprehensive Pharmacology 7

Volume Set - eBook PDF

ASSOCIATE EDITOR IN CHIEF

Copyright Ó 2022 Elsevier Inc. All rights reserved

Library of Congress Cataloging-in-Publication Data

British Library Cataloguing-in-Publication Data

For information on all publications visit our website at

Publisher: Oliver Walter

Associate Editor In Chief

Stephen PH Alexander Lisa Cheng

Robert S Foti Margaret O James

Jordi Ortiz Philip Sandoval

Robert J. Lefkowitz, MD, Nobel laureate

1.10 Kinetics of Drug-Target Binding: A Guide for Drug Discovery 227

1.28 ADME of Biologicals and New Therapeutic Modalities 716

Comprehensive Pharmacology, Volume 1 https://doi.org/10.1016/B978-0-12-820472-6.00194-8 1

1.02.1 An introduction to NC-IUPHAR 4

1.02.1 An introduction to NC-IUPHAR

Table 1 Chairs of NC-IUPHAR past and present.

Term Chair Location

1989–1998 Paul Vanhoutte Paris, France

4 Comprehensive Pharmacology, Volume 1 https://doi.org/10.1016/B978-0-12-820472-6.00178-X

3. Designating polymorphisms and variants which are functionally important;

1.02.2 Membership, aims and objectives of NC-IUPHAR

1.02.3 Outputs from NC-IUPHAR

Fig. 1 The NC-IUPHAR network.

1.02.3.1 Pharmacological reviews

1.02.3.2 British Journal of Pharmacology

Pharmacol Rev BJP

1.02.3.4 GuidetoPharmacology.org (Twitter @GuidetoPHARM)

1.02.4 Reflections on nomenclature successes and “failures”

Table 2 Nomenclature of opioid and opioid-related receptors (Cox et al., 2015).

m, mu, or MOP MOR, OP3 b-Endorphin

1.02.5 Future challenges

10 Comprehensive Pharmacology, Volume 1 https://doi.org/10.1016/B978-0-12-820472-6.00135-3

Fig. 1 Architecture of the 20 RTK subfamilies.

1.03.2 Architecture of RTK extracellular domains

1.03.3 Overview of RTK kinase anatomy and function

1.03.4 ATP binding and the act of phosphorylation

1.03.4.1 Post-Kinase domains

1.03.4.2 Overview of ligands

1.03.5 Types of Inhibitors and how they work

1.03.6 Ligand traps

1.E. Unless you have removed all references to Project Gutenberg:

1.E.1. The following sentence, with active links to, or other

1.E.2. If an individual Project Gutenberg™ electronic work is derived

1.E.3. If an individual Project Gutenberg™ electronic work is posted

1.E.4. Do not unlink or detach or remove the full Project

1.E.5. Do not copy, display, perform, distribute or redistribute this

1.E.7. Do not charge a fee for access to, viewing, displaying,

1.E.8. You may charge a reasonable fee for copies of or providing

• You provide a full refund of any money paid by a user who

• You provide, in accordance with paragraph 1.F.3, a full refund of

1.E.9. If you wish to charge a fee or distribute a Project Gutenberg™

1.F.1. Project Gutenberg volunteers and employees expend

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you

1.F.5. Some states do not allow disclaimers of certain implied

1.F.6. INDEMNITY - You agree to indemnify and hold the

Section 2. Information about the Mission of

Volunteers and financial support to provide volunteers with the

The Foundation’s business office is located at 809 North 1500 West,

Section 4. Information about Donations to