Alice Lanne; Laura E. J. Usselmann; Poppy Llowarch; Lacovos N. Michaelides; Martin Fillmore; Geoffrey A. Holdgate
Drug. Discov. Today, 2023, 103670
https://doi.org/10.1016/j.drudis.2023.103670

Abstract

Recently, there has been a change in the types of drug target entering early drug discovery portfolios. A significant increase in the number of challenging targets or which would have historically been classed as intractable has been observed. Such targets often have shallow or non-existent ligand-binding sites, can have disordered structures or domains or can be involved in protein–protein or protein–DNA interactions. The nature of the screens required to identify useful hits has, by necessity, also changed. The range of drug modalities explored has also increased and the chemistry required to design and optimise these molecules has adapted. In this review, we discuss this changing landscape and provide insights into the future requirements for small-molecule hit and lead generation.