Exploration of a binding mode of benzothiazol-2-yl acetonitrile pyrimidine core based derivatives as potent c-Jun N-terminal kinase-3 inhibitors and 3D-QSAR analyses
Metadata of CSIR Papers
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| Title |
Exploration of a binding mode of benzothiazol-2-yl acetonitrile pyrimidine core based derivatives as potent c-Jun N-terminal kinase-3 inhibitors and 3D-QSAR analyses
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| Creator |
Sharma, P
Ghoshal, N |
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| Subject |
Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications
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| Description |
C-Jun N-terminal kinase (JNK) is a therapeutic target for inhibitors which may provide clinical benefit in the pathogenesis of rheumatoid arthritis ( RA) as well as in various apoptosis-related disorders. The benzothiazol-2-yl acetonitrile derivatives, recently reported by Pascale et al. (J. Med. Chem. 2005, 48, 45964607), are the first generation JNK inhibitors of this class. To understand inhibitory mechanisms and elucidate pharmacophoric properties of these derivatives molecular docking and 3D-QSAR studies were performed on a set of 44 compounds. Ligand Fit module of Cerius2 (4.9) was employed to locate the binding orientations of all the compounds within the JNK-3 ATP binding site. A good correlation (r(2) = 0.810) between the calculated binding free energies (-PMF score) and the experimental inhibitory activities suggests that the identified binding conformations of these potential inhibitors are reliable. Based on the binding conformations, robust and highly predictive 3D-QSAR models were developed with conventional r(2) 0.886 and 0.802, full cross-validation r(2) 0.980 and 0.788, and predictive r(2) 0.965 and 0.968 for MFA and MSA, respectively. The interaction mode was demonstrated taking into consideration inhibitor conformation, hydrogen bonding, and electrostatic interaction. The 3D-QSAR model built in this study will provide clear guidelines for a novel inhibitor design based on the benzothiazole derivatives against JNK-3 for the treatment of inflammatory disorders.
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| Publisher |
AMER CHEMICAL SOCWASHINGTON1155 16TH ST, NW, WASHINGTON, DC 20036 USA
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| Date |
2011-09-20T12:12:11Z
2011-09-20T12:12:11Z 2006 |
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| Type |
Article
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| Identifier |
JOURNAL OF CHEMICAL INFORMATION AND MODELING
1549-9596 http://hdl.handle.net/123456789/14160 |
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| Language |
English
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