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Off-Pocket Activity Cliffs: A Puzzling Facet of Molecular Recognition

While accurate quantitative prediction of ligand-protein binding affinity remains an elusive goal, high-affinity ligands to therapeutic targets are being designed through heuristic optimization of ligand-protein contacts. However, herein, through large-scale data mining and analyses, we demonstrate that a ligand's binding can also be strongly affected through modifying its solvent-exposed portion that does not make any contacts with the protein. We called this phenomenon "off-pocket activity cliffs" (OAC). We then exposed the solvent-dependent nature of the AAC phenomenon by means of molecular dynamics (MD) simulations and MD data analyses. We expect AAC to extend our knowledge of molecular recognition and enhance the drug designer's toolkit.