Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT

ABSTRACT - Internet Electron. J. Mol. Des. December 2007, Volume 6, Number 12, 385-395

Comparative Molecular Field Analysis (CoMFA) for p38 Inhibitors Munuganti Ravi Shashi Nayana and Yadavalli Nataraja Sekhar Internet Electron. J. Mol. Des. 2007, 6, 385-395

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Abstract:
The p38 kinase plays a vital role in the inflammation mediated by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) pathways and inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Three dimensional quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) were performed on 38 benzimidazolone derivatives as p38 kinase inhibitors. CoMFA was performed using Sybyl software 6.7v. Compounds were divided in to training and test set. The developed model based on training set containing 28 compounds gave leave one out cross validation q² value of 0.648 and non cross validation r² value of 0.980 and standard error of estimate 0.119 for CoMFA. The steric and electrostatic contributions are 61.6% and 38.4%. Additionally, the binding mode of the high active compound at the active site of p38 MAP alpha kinase was explored using LigandFit docking program and hydrogen-bonding interactions were observed between the inhibitor and the target. The details of amino acid interactions of the active site are discussed briefly. The CoMFA model provided the most significant correlation of steric and electrostatic fields with biological activities. The information rendered by 3D QSAR model may afford valuable clues to optimize the lead and design new potential inhibitors.

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