Assessing Protein Kinase Selectivity with Molecular Dynamics and MM‐PBSA Binding Free Energy Calculations

An application of molecular dynamics and molecular mechanics Poisson-Boltzmann surface area techniques to the prediction of protein kinase inhibitor selectivity is presented. A highly active and selective ERK2 inhibitor was placed in equivalent orientations in five different protein kinases (SRC, LCK, GSK3, JNK3 and Aurora-A). Binding free energies were then computed with the molecular mechanics Poisson-Boltzmann surface area approach using 15 nanosecond fully solvated molecular dynamics trajectories of the corresponding protein-ligand complexes. The results show correlation with experimentally determined selectivities and provide useful insights into the underlying structural determinants for selectivity.