Applied Biophysical Methods in Fragment-Based Drug Discovery

Abstract

Fragment-based drug discovery (FBDD) has come of age in the last decade with the FDA approval of four fragment-derived drugs. Biophysical methods are at the heart of hit discovery and validation in FBDD campaigns. The three most commonly used methods, thermal shift, surface plasmon resonance, and nuclear magnetic resonance, can be daunting for the novice user. We aim here to provide the nonexpert user of these methods with a summary of problems and challenges that might be faced, but also highlight the potential gains that each method can contribute to an FBDD project. While our view on FBDD is slightly biased toward enabling structure-guided drug discovery, most of the points we address in this review are also valid for non-structure-focused FBDD.

NMR as a “Gold Standard” Method in Drug Design and Discovery

“…FBDD is a main-stream screening technique for drug discovery [ 207 , 209 , 211 , 212 , 213 , 214 , 215 , 216 ] and NMR is standard for many FBDD studies [ 209 ]. Additional methods and techniques such as SPR, X-ray crystallography [ 209 , 217 , 218 , 219 , 220 ] etc. have also been used in FBDD studies, accompanied or unaccompanied by NMR experiments.…”

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

“…The NMR spectroscopy is the most robust fragment screening method for detecting very weak binding (K D s in the µM to mM range). The NMR approach used to identify target-ligand interactions can be based on observation of the target (targetobserved) or ligand (ligand-observed) (195). In the case of ligand-observed NMR methods, only the resonance of the nuclei present in the ligands is measured (196).…”

Fast Mek1 Hit Identification with TRIC Technology Correlates Well with Other Biophysical Methods

“…Although FBS is widely used in drug discovery, some challenges remain when it comes to building a steady and reliable workflow. 2 Fragments are low-molecular-weight compounds and thus require a detection method that is independent of mass. Since fragments show weak affinities and sometimes low solubility at high concentration, instruments need to be able to tolerate compound precipitation or great care is needed during experimentation.…”

“…These and other parameters of FBS elicit the need for orthogonal and parallel detection technologies to yield reliable hit confirmation. 2,3 For targets without biochemical activity, researchers look for biophysical methods as alternatives, but even with smaller library sizes, fast methods are needed, often a weak spot of biophysical techniques.…”