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
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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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, Pooja
Ghoshal, Nanda |
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| Subject |
Drug Development/Diagnostics & Biotechnology
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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, 4596- 4607), 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 (r2)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 r2 0.886 and 0.802, full
cross-validation r2 0.980 and 0.788, and predictive r2 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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| Date |
2006
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/488/1/JOURNAL_OF_CHEMICAL_INFORMATION_AND_MODELING%2C_46(_4)%2C_1763%2D1774_%2C2006_[59].pdf
Sharma, Pooja and Ghoshal, Nanda (2006) 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. J. Chem. Inf. Model., 46 (4). pp. 1763-1774. |
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| Relation |
htpp://dx.doi.org/10.1021/ci060057q
http://www.eprints.iicb.res.in/488/ |
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