Predicting the Binding Affinity of P38 Map Kinase Inhibitors using Free Energy Calculations

Abstract

The major challenge of drug design efforts is focused on inhibitors of p38 MAP kinase (MAPK14) proteins to develop the drug resistance caused by spontaneous mutations in the kinase domain. Despite the central role in structure-based drug design of kinase in order to determine the position, orientation and conformation of small inhibitors in protein, we investigated how DFG (Asp-Phe-Gly)-in and DFG-out active sites are important in type I inhibitor binding to ATP site of kinase. The investigation has been focused on the key interaction as hydrogen bond and pi-stacking, based on molecular dynamics (MD) simulations. Moreover, the thermodynamic integration (TI) free energy calculations has been used to identify the type II inhibitors which are stable binding to the allosteric site of p38 MAP kinase. Diaryl urea of type II inhibitor showed to be involved in an extensive hydrogen bond network and proved critical for binding activity. TI free energy calculations are in agreement with the experiment. The results confirmed that interaction with type II inhibitors is compatible with DFG-out conformation of p38 MAP kinase. Therefore, the MD simulations can successfully predict the interaction of inhibitors in P38 MAP kinase and determine the differences in binding affinity which can be helpful to develop new type II inhibitors for the treatment of many diseases.