Revealing the molecular mechanism of different residence times of ERK2 inhibitors via binding free energy calculation and unbinding pathway analysis

SCH772984, VTX-11e, FR180204 and 5-iTU are four promising inhibitors targeting ERK2 kinase with high bioactivity. These four inhibitors also have different residence times and binding modes with the ERK2 kinase. Revealing the molecular mechanism of different residence times of ERK2 inhibitors is helpful for designing more efficient inhibitors. The molecular mechanics/generalized Born surface area (MM/GBSA) method was used to calculate the binding free energy and identify the key residues for the ERK2 protein binding to the four inhibitors. Steered molecular dynamics (SMD) and adaptive biasing force (ABF) simulations were employed to investigate the molecular mechanism behind this difference in residence time and binding mode. The binding free energy decomposition by the MM/GBSA method reveals the residues Y27, K45, 147, P49, Y55, R58, T59, Q96 and G160 located around the allosteric binding pocket play an important role in determining the longer residence time of SCH772984. The results from the SMD and the ABF simulations show SCH772984 has different unbinding mechanism compared with the other three inhibitors. SCH772984 needs to overcome two energy barriers: one is the pi-pi stacking interaction formed by the piperazine-phenyl-pyrimidine of SCH772984 and the residue Y55 of the ERK2 kinase; the other is the hydrophobic interaction at the ATP active site. VTX-11e, FR180204 and 5-iTU just need to overcome the hydrophobic interaction at the ATP active site. Our simulation results are useful to understand the interaction mechanism between four inhibitors and ERK2 kinase and are helpful for designing more potent ERK2 inhibitors. (C) 2016 Elsevier B.V. All rights reserved.