Polypharmacology rescored: Protein-ligand interaction profiles for remote binding site similarity assessment

Current methods to characterize and compare structure-based interaction patterns - both for protein-small-molecule and protein-protein interactions - as well as their potential in target prediction will be reviewed in this article. The question of how the set of interaction types, flexibility or water-mediated interactions, influence the comparison of interaction patterns will be discussed. Due to the wealth of protein-ligand structures available today, predicted targets can be ranked by comparing their ligand interaction pattern to patterns of the known target. Such knowledge-based methods offer high precision in comparison to methods comparing whole binding sites based on shape and amino acid physicochemical similarity.