Off-Pocket Activity Cliffs: A Puzzling Facet of Molecular Recognition
Tigran M. Abramyan, Yi An, Dmitri Kireev · Journal of Chemical Information and Modeling · 2019
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 contacts with the protein, thus resulting in “off-pocket activity cliffs” ( OAC ). We then exposed the roots of the OAC phenomenon by means of molecular dynamics ( MD ) simulations and MD data analyses. We expect OAC to extend our knowledge of molecular recognition and enhance the drug designer’s toolkit.