Targeting protein-protein interactions with small molecules: Challenges and perspectives for computational binding epitope detection and ligand finding

A promising way to interfere with biological processes is through the control of protein-protein interactions by means of small molecules that modulate the formation of protein-protein complexes. Although the feasibility of this approach has been demonstrated in principle by recent results, many of the small-molecule modulators known to date have not been found by rational design approaches. In large part this is due to the challenges that one faces in dealing with protein binding epitopes compared to, e.g., enzyme binding pockets. Recent advances in the understanding of the energetics and dynamics of protein binding interfaces and methodological developments in the field of structure-based drug design methods may open up a way to apply rational design approaches also for finding protein-protein interaction modulators. These advances and developments include (1) computational approaches to dissect binding interfaces in terms of energetic contributions of single residues (to identify hot spot residues), (11) prediction of potential binding sites from unbound protein structures, (111) recognition of allosteric binding sites as alternatives to directly targeting interfaces, (IV) docking approaches that consider protein flexibility and improved descriptions of the solvent influence on electrostatic interactions, and (V) data-driven docking approaches. Here, we will summarize these, developments with a particular emphasis on their applicability to screen for or design small-molecule modulators of protein-protein interactions.