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3D-QSAR and Molecular Docking Studies on Fused Pyrazoles as p38α Mitogen-Activated Protein Kinase Inhibitors
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University ,Guangzhou 510632, Guangdong, China
* Author to whom correspondence should be addressed.
Received: 6 July 2010; Accepted: 3 September 2010 / Published: 17 September 2010
Abstract: The p38α mitogen-activated protein kinase (MAPK) has become an attractive target for the treatment of many diseases such as rheumatoid arthritis, inflammatory bowel disease and Crohn’s disease. In this paper, 3D-QSAR and molecular docking studies were performed on 59 p38α MAPK inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to determine the structural requirements for potency in inhibiting p38α MAPK. The resulting model of CoMFA and CoMSIA exhibited good r2cv values of 0.725 and 0.609, and r2 values of 0.961 and 0.905, respectively. Molecular docking was used to explore the binding mode between the inhibitors and p38α MAPK. We have accordingly designed a series of novel p38α MAPK inhibitors by utilizing the structure-activity relationship (SAR) results revealed in the present study, which were predicted with excellent potencies in the developed models. The results provided a useful guide to design new compounds for p38α MAPK inhibitors.
Keywords: p38α mitogen-activated protein kinase; 3D-QSAR; CoMFA; CoMSIA; docking
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Lan, P.; Huang, Z.-J.; Sun, J.-R.; Chen, W.-M. 3D-QSAR and Molecular Docking Studies on Fused Pyrazoles as p38α Mitogen-Activated Protein Kinase Inhibitors. Int. J. Mol. Sci. 2010, 11, 3357-3374.
Lan P, Huang Z-J, Sun J-R, Chen W-M. 3D-QSAR and Molecular Docking Studies on Fused Pyrazoles as p38α Mitogen-Activated Protein Kinase Inhibitors. International Journal of Molecular Sciences. 2010; 11(9):3357-3374.
Lan, Ping; Huang, Zhi-Jian; Sun, Jun-Rong; Chen, Wei-Min. 2010. "3D-QSAR and Molecular Docking Studies on Fused Pyrazoles as p38α Mitogen-Activated Protein Kinase Inhibitors." Int. J. Mol. Sci. 11, no. 9: 3357-3374.