Fragment‐Based Lead Discovery

Abstract

Fragment‐based discovery is an effective approach to finding hit compounds that bind to a target. Fragments can be found that bind to most sites on most proteins, providing a rich source of chemical ideas for the medicinal chemist to develop into hits and leads. There are two distinctive activities in fragment‐based discovery: (i) finding fragments that bind and (ii) evolving the fragments to hit compounds which can then be progressed using conventional (structure‐guided) optimization. A wide variety of methods have been developed for screening, many based on biophysical approaches to identify and then characterize the binding of the relatively low affinity (but efficient) compounds – a separate section summarizes the key features of the methods. Perhaps the most difficult aspect of fragment‐based discovery is deciding which fragments to evolve – another section describes some recent projects to highlight the key strategies that are used. The article concludes with some summary statements on the main features and advantages of the approach and a discussion about future directions.

Reactive Docking: A Computational Method for High-Throughput Virtual Screenings of Reactive Species

“…Here, we demonstrate that in a fully predictive setting (i.e., neither the site nor the ligand is known in advance), the method can provide an enrichment of binders (particularly strong binders) comparable to focused conventional virtual screenings. While the use of a fragment library for assessing the VS performance is intrinsically more challenging compared to drug-like ligands, 39 the overall results in simultaneous prediction of both residue and ligands suggest that this protocol is very suitable for prospective VS campaigns.…”