Protein-ligand interaction fingerprints for accurate prediction of dissociation rates of p38 MAPK Type II inhibitors.

Binding/unbinding kinetics are key determinants of drug potencies. However, there are still a lot of challenges in predicting kinetic properties during early-stage drug development. In this work, position-restrained molecular dynamics simulations combined with energy decomposition were applied to extract protein-ligand interaction (PLI) fingerprints along the unbinding pathway of 20 p38 mitogen-activated protein kinase (p38 MAPK) Type II inhibitors. The results showed that the electrostatic and/or van der Waals interaction fingerprints at three key positions can be used for accurate prediction of the dissociation rate constants (koff) of p38 MAPK Type II inhibitors. The strategy proposed in this paper can provide not only an efficient method of predicting the dissociation rates of the p38 MAPK Type II inhibitors, but also the atom-level mechanism of enthalpy-driven unbinding process.