3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38[alpha] mitogen-activated protein kinase inhibitors

Mol Divers (2012) 16:377388 DOI 10.1007/s11030-011-9353-y

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3D-QSAR and molecular docking analysis of biphenyl amide derivatives as p38 mitogen-activated protein kinase inhibitors

Pravin Sundarao Ambure Rahul Prakashchand Gangwal

Abhay T. Sangamwar

Received: 12 September 2011 / Accepted: 22 December 2011 / Published online: 7 January 2012 Springer Science+Business Media B.V. 2012

Abstract The p38 mitogen-activated protein (MAP) kinase plays a vital role in treating many inammatory diseases such as rheumatoid arthritis, inammatory bowel disease, Crohns 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 elds. The resulting model from CoMFA and CoMSIA exhibited excellent r2ncv values of 0.979 and 0.942, and r2cv values of 0.766 and 0.748, respectively. CoMFA predicted r2pred of 0.987 and

CoMSIA predicted r2pred 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 p38 MAP kinase. We have accordingly designed novel p38 MAP kinase inhibitors by utilizing LeapFrog and predicted with excellent activity in the developed models.

Keywords p38 MAP kinase Biphenyl amide CoMFA

CoMSIA Molecular docking LeapFrog Glide

Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s11030-011-9353-y

Web End =10.1007/s11030-011-9353-y ) contains supplementary material, which is available to authorized users.

Pravin Sundarao Ambure and Rahul Prakashchand Gangwal contributed equally to this study.

P. S. Ambure R. P. Gangwal A. T. Sangamwar (B)

Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sect-67, S.A.S. Nagar 160062, Punjab, Indiae-mail: [email protected]

Introduction

The p38 MAP kinase is a serine/threonine kinase, which plays a crucial role in many inammatory diseases such as rheumatoid arthritis [1], inammatory bowel disease [2], Crohns disease [3], and psoriasis [4]. It was rst identied in human monocytes as the target for a class of cytokine suppressive anti-inammatory compounds [5]. Four variants of p38 kinase have been documented, namely, p38 (also known as p38), p38, p38 (ERK6/SAPK3), and p38 (SAPK4) with 4060% structural similarity [68], while the roles of p38, p38 and p38...