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. Sharma, P. & Ghoshal, N. J.~Chem.~Inf.~Model., 46(4):1763--1774, Drug Design, Development and Molecular Modeling Division, Indian Institute of Chemical Biology (CSIR), 4 Raja S.C.Mullick Road, Jadavpur, Kolkata -700032, India., 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. [link]Paper  doi  abstract   bibtex   
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.
@article{Sharma:2006zr,
	Abstract = {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.},
	Address = {Drug Design, Development and Molecular Modeling Division, Indian Institute of Chemical Biology (CSIR), 4 Raja S.C.Mullick Road, Jadavpur, Kolkata -700032, India.},
	Au = {Sharma, P and Ghoshal, N},
	Author = {Sharma, Pooja and Ghoshal, Nanda},
	Da = {20060724},
	Date-Added = {2007-12-11 17:01:03 -0500},
	Date-Modified = {2007-12-11 17:01:03 -0500},
	Dcom = {20060920},
	Doi = {10.1021/ci060057q},
	Edat = {2006/07/25 09:00},
	Issn = {1549-9596 (Print)},
	Jid = {101230060},
	Journal = {J.~Chem.~Inf.~Model.},
	Jt = {Journal of chemical information and modeling},
	Keywords = {binding mode conformation 3d QSAR JNK-3},
	Language = {eng},
	Lr = {20061115},
	Mhda = {2006/09/21 09:00},
	Number = {4},
	Own = {NLM},
	Pages = {1763--1774},
	Pl = {United States},
	Pmid = {16859308},
	Pst = {ppublish},
	Pt = {Journal Article; Research Support, Non-U.S. Gov't},
	Pubm = {Print},
	Rn = {0 (Benzothiazoles); 0 (Enzyme Inhibitors); 0 (Pyrimidines); 0 (Thiazoles); 95-16-9 (benzothiazole); EC 2.7.1.- (Mitogen-Activated Protein Kinase 10)},
	Sb = {IM},
	So = {J.~Chem.~Inf.~Model.. 2006 Jul-Aug;46(4):1763-74.},
	Stat = {MEDLINE},
	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.},
	Url = {http://dx.doi.org/10.1021/ci060057q},
	Volume = {46},
	Year = {2006},
	Bdsk-Url-1 = {http://dx.doi.org/10.1021/ci060057q},
	Bdsk-Url-2 = {http://dx.doi.org/10.1021/ci060057q}}
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