Structure-based virtual screening approach to the discovery of p38 MAP kinase inhibitors

Abstract

p38 Mitogen-activated protein kinase (MAPK) has been considered to be a promising target for the development of therapeutics for various immunologic diseases. Herein we report an example for a successful application of the virtual screening with protein-ligand docking to identify the novel inhibitors of p38 alpha MAPK. These inhibitors were screened for having desirable physicochemical properties as a drug candidate and compound 1-3 revealed a moderate inhibitory activity with IC50 values ranging from 0.7 to 20 mu M. Therefore, they deserve a consideration for further development by structure-activity relationship (SAR) studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of p38 MAPK are addressed in detail. (C) 2012 Elsevier Ltd. All rights reserved.