3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38α mitogen-activated protein kinase inhibitors

摘要

The p38α mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and psoriasis. Herein, we have performed 3D-QSAR and molecular docking analysis on a novel series of biphenyl amides to design potent p38 MAP kinase inhibitors. This study correlates the p38 MAP kinase inhibitory activities of 80 biphenyl amide derivatives to several stereochemical parameters representing steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields. The resulting model from CoMFA and CoMSIA exhibited excellent r ~2 _(ncv) values of 0.979 and 0.942, and r ~2 _(cv) values of 0.766 and 0.748, respectively. CoMFA predicted r ~2 _(pred) of 0.987 and CoMSIA predicted r ~2 _(pred) of 0.761 showed that the predicted values were in good agreement with experimental values. Glide (5.5) program gave the path for binding mode exploration between the inhibitors and p38α MAP kinase. We have accordingly designed novel p38α MAP kinase inhibitors by utilizing LeapFrog and predicted with excellent activity in the developed models.