Detailed atomistic molecular modeling of a potent type ΙΙ p38α inhibitor

The active site conservation among protein kinases makes it a real challenge to design selective inhibitors. In this regard, detailed understanding of structural features responsible for functional behavior of different protein kinases is an important challenge in structure-based drug design. Amino acid decomposition analysis (ADA) is a powerful method to recognize and evaluate possible binding loci (hot spots) in ligand–receptor interaction. These hot spots could be used as a tool to differentiate selectivity profiles among similar protein kinases. p38a is a prominent target in the development of new anti-inflammatory agents. Type II p38a inhibitors bind to DFG-out conformation of p38a in its inactive form. We performed a computational approach including MD simulations and ab initio method to evaluate a type II p38a inhibitor. MD simulation was used to evaluate the binding pattern between ligand and p38a active site residues. Penetration of ligand thorough lipid bilayer was assessed by MD simulation using DPPC as a lipid bilayer model. Further conformational analysis was applied to determine induced ligand conformational instability due to binding to the receptor. ADA provided interesting results for pharmacophore discrimination. According to obtained results, residues Asp168, Leu167, Met109 and Glu71 had most contribution in binding to ligand. Conformational analysis showed that diffusion of ligand through lipid bilayer is done almost in nearly optimum structure. The obtained results could reveal some information on molecular basis of p38a inhibition, while being in good agreement with proposed pharmacophore in the literature