David Witty’s Post

In this episode of The Chain, GlaxoSmithKline’s Rajesh Sundaresan, PhD, speaks with Thomas P. Sakmar, MD, Professor of Chemical Biology at Rockefeller University, about the history of GPCRs and various subunits, his early work with rhodopsin, and the impact of crystallography and structural work. He also shares how he got started with molecular biology training, as well as his thoughts on the state-of-the art for both biologics and small molecules in drug discovery. Listen to the conversation: https://lnkd.in/d54Dsq64

This summer I was awarded a full scholarship to join the 2023 cohort of Drew University's Residential School on Medicinal Chemistry and Biology in Drug Discovery (#RESMED). In this five-day seminar course, scientists from pharma/biopharma shared their knowledge, time-tested techniques, and insights for turning biological ideas into viable clinical products. Here are three of my favorite lectures and their respective takeaways: Talk #1: Pfizer's Dafydd Owen on the molecular design of Paxlovid (Nirmatrelvir) as a COVID-19 3CL protease inhibitor. Takeaway #1: Substrate mimicry is a time-tested and strong technique for rational structure-based drug design. This lecture further enhanced my appreciation for a drug that I as a pharmacy rotation student dosed and dispensed to patients with life-threatening COVID-19. Talk #2: Merck's Randy Miller on pharmacokinetics and plasma protein binding. Takeaway #2: THE FREE-DRUG HYPOTHESIS, during drug discovery/development don't worry about total serum concentrations, it is the unbound drug that drives pharmacodynamic effects, is consistent tissue-to-tissue, and is available for metabolism/excretion. Talk #3: Harvard's Mark Namchuk on enzymology and receptor binding. Takeaway #3: Don't be afraid to dig into mechanisms and kinetics, binding energy/conformation are what directly allows for enzymatic accelerations to reaction rates. The lower limit of Ki/IC50 assays is determined by ENZYME CONCENTRATION. Lastly, biased agonism may play an impressive role in the future of molecular pharmacology. Very thankful to the team at Drew University for allowing me to join this prestigious course, and to my research mentor Sunil Kumar, Ph.D. for his continual support and guidance.

Drug discovery is a tedious and expensive process that takes time and specially costs plus uncertainly in finding the right molecules. The space of potential drug-like molecules is huge and difficult to have precisse methods from achieving any reasonable effectiveness. There are many new active search techniques that have been increasing in popularity in recent years as a method for accelerating the discovery of novel pharmaceutical molecules. By providing an effective method for prioritizing molecules within the discovery process, the efficiency of the discovery process can be dramatically improved.

I am happy to share that a long awaited article published in progress in Molecular Biology and Translational Science (Impact Factor = 3.6) "System biology approaches for drug repurposing" #Drug repurposing #Medication repurposing #Drug development #Network biology #System biology #Innovation #Healthcare

Don't miss the chance to engage with Dr. Karim Azer, the head of the Systems Biology Platform & Discovery at Axcella Therapeutics, at the 10th Drug Discovery Strategy Meeting on November 7 in Boston. With a career spanning over two decades in the pharmaceutical industry, Karim brings a wealth of experience to the table. He has led efforts in quantitative sciences, computational biology, systems pharmacology, modeling, and data science at prestigious organizations like the Bill & Melinda Gates Medical Research Institute, Merck, and Sanofi. Karim's discussion, "Unraveling Drug-Target Interactions: Advancements in In Silico Modeling and Simulation," promises to be illuminating. In this session, you'll gain insights into how in silico modeling and simulation techniques have revolutionized our understanding of drug-target interactions, shedding light on the mechanisms of action for new drug candidates and their clinical translation. Discover how the integration of machine learning and artificial intelligence can further enhance our comprehension of these interactions, potentially leading to the discovery of novel targets and drug candidates. While remarkable progress has been made, there are still challenges on the horizon. Join Karim and fellow industry leaders as they explore the future of in silico modeling in drug discovery. It's an opportunity to be at the forefront of cutting-edge advancements!  Register now with code VIPKARIM for a FREE VIP Pass and be part of this transformative discussion. https://lnkd.in/g2jdThUp *To be eligible for a VIP PASS, you must be from a drug-developing company that has a current and public drug pipeline or be in a full-time academic position, that does not offer any paid-for service or solutions #DrugDiscovery #StrategyMeeting #Proventa10Years #InSilicoModeling #Pharmaceuticals

What can we expect from GPCRs in antibodies and biologics? In this episode of The Chain Podcast, host Sundaresan Rajesh, Scientific Leader and GSK Fellow of Protein Cell and Structural Sciences at GSK, speaks with Thomas Sakmar, Professor of Chemical Biology at The Rockefeller University, about the history of #GPCRs and various subunits, his early work with rhodopsin, and the impact of #crystallography and structural work. He also shares how he got started with molecular biology training, as well as his thoughts on the state-of-the art for both #biologics and small molecules in #drugdiscovery. https://lnkd.in/gtDnrsCY

GPCRs such as 5-HT are triggered by low MW ligands which all apparently bind in the same pocket and in the same binding mode across this class of GPCRs and yet give widely different pharmacological effects. The easy part in GPCRs is making potent binders and seemingly selective (pharmacology) molecules in cell based assays, so computation seems to perform well in early stages of the program. The main challenge is the disconnect between cellular assay and PK/PD. GPCR drug discovery really starts when you are doing your first PK/PD measurement and basically hope for the best result. Papers such as this highlights how difficult it is to make GPCR drugs. Nice one to read over a coffee. #drugdiscovery #machinelearning #computationalchemistry #venturecapital #gpcr #pharmacology

🔬 CYNBIOSE is thrilled to have been part of a project aimed at enhancing the reproducibility and comparability of primate imaging research, a species of particular relevance in evaluating the pharmacology and neurotoxicity of novel pharmaceuticals.   This database provides reliable baseline data for imaging studies using macaques, helping scientists design leaner protocols with smaller control groups and contributing to the broader efforts of the scientific community in support of the 3R principles (Replacement, Reduction, Refinement).   🌐 This achievement highlights Cynbiose's dedication to advancing scientific innovation and advocating for more ethical research practices, showcasing how the synergy of public and private partnerships drives the progress of scientific knowledge.   👉 Read the article: https://bit.ly/48Sovpz   Laboratoire CarMeN INRAE UMR1397-INSERM U1060 Olea Medical - Improved Diagnosis for Life Institut des Sciences Cognitives Marc Jeannerod, UMR 5229 CNRS CERMEP Hospices Civils de Lyon - HCL Laboratoire CREATIS UMR_CNRS_INSERM #preclinical #pharmacology #neurotoxicity