Abstract

Fragment-based drug discovery (FBDD) is now established as a complementary approach to high-throughput screening (HTS). Contrary to HTS,
where large libraries of drug-like molecules are screened, FBDD screens involve smaller and less complex molecules which, despite a low affinity to
protein targets, display more ‘atom-efficient’ binding interactions than larger molecules. Fragment hits can, therefore, serve as a more efficient start point for subsequent optimisation, particularly for hard-to-drug targets. Since the number of possible molecules increases exponentially with molecular size, small fragment libraries allow for a proportionately greater coverage of their respective ‘chemical space’ compared with larger HTS libraries
comprising larger molecules. However, good library design is essential to ensure optimal chemical and pharmacophore diversity, molecular complexity, and physicochemical characteristics. In this review, we describe our views on fragment library design, and on what constitutes a good fragment from a medicinal and computational chemistry perspective. We highlight emerging chemical and computational technologies in FBDD and discuss
strategies for optimising fragment hits. The impact of novel FBDD approaches is already being felt, with the recent approval of the covalent KRASG12C inhibitor sotorasib highlighting the utility of FBDD against targets that were long considered undruggable.

By Marta Bon, Alan Bilsland, Justin Bower & Kirsten McAulay