Protein-protein interactions play key roles in all biological processes, motivating numerous
campaigns to seek small-molecule disruptors of therapeutically relevant interactions. Two decades
ago, the prospect of developing small-molecule inhibitors was thought to be perhaps impossible due
to the potentially undruggable nature of the protein surfaces involved; this viewpoint was reinforced
by the limited successes provided from traditional high-throughput screens. To date, however, refinement
of new experimental approaches has led to a multitude of inhibitors against many different
targets. Having thus established the feasibility of attaining success in this valuable and diverse target
space, attention now turns to incorporating computational techniques that might assist during various
stages of drug design and optimization. Here we review cases in which computational approaches –
virtual screening, docking, and ligand optimization – have contributed to discovery of new inhibitors
of protein-protein interactions. We conclude by providing an outlook into the upcoming challenges
and recent advances likely to shape this field moving forward.
Keywords: Virtual screening, Ligand docking, Protein-protein interaction, Drug design, Protein pocket, HTS.
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