Advances in Biophysical Hit Validation in Drug Discovery

All drug discovery is predicated on finding lead molecules which can be further optimized for potency, pharmacokinetics, pharmacodynamics, and safety. These leads almost always begin with a screen for molecules (small molecule, peptide, or even biologics) which meet or exceed a threshold level of desired bioactivity. Despite advances in screening technologies, which now include high-throughput in vitro, cell-based, biophysical interaction (e.g. Affinity-Selection Mass Spectrometry, or ASMS), and DNA-Encoded Library (DEL) screening methods, a key hurdle is demonstrating bona fide physical engagement of the screening hits with the biological target of interest. Current estimates of target engagement confirmation are <1-5% of screening hits identified, a shockingly low confirmation rate that spans all screening methods employed.Over the past several decades, numerous biophysical workflows have been employed to demonstrate target engagement of screening hits. The goal of this collection is both to review specific biophysical techniques as well as to highlight new developments in hit validation. We hope to empower researchers in both academia and the biopharmaceutical industry with our years of experience in handling and triaging screening hits for drug discovery. By doing so, we aim to help researchers focus their optimization efforts on the highest quality, most likely to succeed, lead molecules in their drug discovery efforts.This Topic focuses on biophysical validation of target engagement for screening hits in drug discovery. We welcome submissions on themes including, but not limited to:● Review of the problem of validating screening hits and specific techniques for biophysical validation of target engagement● Various logic systems for assessing development risk for screening hits, such as the “Validation Cross”● Analysis or application of legacy techniques including SPR, ASMS, BALI-MS, thermal shift analysis, and MST● Analysis or application of techniques for hit validation in membrane proteins, including SPR microscopy, Helix Biosensors, and TSA with CPM dyes● Specialized hit validation workflows for fragment-based screens and DEL selection campaigns● Frontier methods, such as Flow-Induced Dispersion Analysis, for assessing target-ligand engagementTopic Editor Felix Vajdos is the founder of Molecular Insights Consulting and is a consultant for Biosensing Instrument. Topic Editor Renaud Prudent is employed by Edelris SAS. Topic Editor Phillip Schwartz is employed by Septerna Inc. Topic editors: Renaud Prudent, Phillip Schwartz, Felix Vajdos Source: https://www.frontiersin.org/research-topics/84705/advances-in-biophysical-hit-validation-in-drug-discovery