Biophysics in drug discovery: impact, challenges and opportunities

Key Points The rapid development of sensitive biophysical methods is transforming drug discovery by providing early profiling of compound properties and insights into mechanisms of action. Biophysical methods are used extensively in hit finding (fragment-based screening and high-throughput screening), hit validation, in depth characterization of compound binding and lead optimization. A growing application of biophysical methods is to understand the relationship between the kinetics of binding, mode of action, and molecular structures and interactions. This has had substantial impact on recognizing the importance of binding kinetics and residence time for therapeutic action. Additional information derived from biophysical methods ranges from protein quality control, quantitative binding data, and determination of ligand–target complex structures to complex mode-of-action studies. The efficient use of these methods requires experience in experimental design and data analysis, and a strategic combination of orthogonal methods. Newly emerging technologies such as cryo-electron microscropy (cryo-EM) for high-resolution determination of massive biological structures and more rapid methods for the characterization of binding kinetics and thermodynamics will further reinforce the importance of biophysics in drug discovery. Over the past 25 years, biophysical technologies such as X-ray crystallography and nuclear magnetic resonance spectroscopy have become key components of drug discovery platforms in many pharmaceutical companies and academic laboratories. This article provides a framework to understand this evolution by describing the key biophysical methods, the information they can provide and the ways they can be applied at different stages of the drug discovery process. Over the past 25 years, biophysical technologies such as X-ray crystallography, nuclear magnetic resonance spectroscopy, surface plasmon resonance spectroscopy and isothermal titration calorimetry have become key components of drug discovery platforms in many pharmaceutical companies and academic laboratories. There have been great improvements in the speed, sensitivity and range of possible measurements, providing high-resolution mechanistic, kinetic, thermodynamic and structural information on compound–target interactions. This Review provides a framework to understand this evolution by describing the key biophysical methods, the information they can provide and the ways in which they can b