TY - JOUR
T1 - Three-dimensional quantitative structure-activity relationship (3 D-QSAR) and docking studies on (benzothiazole-2-yl) acetonitrile derivatives as c-Jun N-terminal kinase-3 (JNK3) inhibitors
AU - Shaikh, Abdul Rajjak
AU - Ismael, Mohamed
AU - Del Carpio, Carlos A.
AU - Tsuboi, Hideyuki
AU - Koyama, Michihisa
AU - Endou, Akira
AU - Kubo, Momoji
AU - Broclawik, Ewa
AU - Miyamoto, Akira
PY - 2006/11/15
Y1 - 2006/11/15
N2 - Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 44 (benzothiazole-2-yl) acetonitrile derivatives, inhibiting c-Jun N-terminal kinase-3 (JNK3). It includes molecular field analysis (MFA) and receptor surface analysis (RSA). The QSAR model was developed using 34 compounds and its predictive ability was assessed using a test set of 10 compounds. The predictive 3D-QSAR models have conventional r2 values of 0.849 and 0.766 for MFA and RSA, respectively; while the cross-validated coefficient rcv2 values of 0.616 and 0.605 for MFA and RSA, respectively. The results of the QSAR model were further compared with a structure-based analysis using docking studies with crystal structure of JNK3. Ligands bind in the ATP pocket and the hydrogen bond with GLN155 was found to be crucial for selectivity among other kinases. The results of 3D-QSAR and docking studies validate each other and hence, the combination of both methodologies provides a powerful tool directed to the design of novel and selective JNK3 inhibitors.
AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 44 (benzothiazole-2-yl) acetonitrile derivatives, inhibiting c-Jun N-terminal kinase-3 (JNK3). It includes molecular field analysis (MFA) and receptor surface analysis (RSA). The QSAR model was developed using 34 compounds and its predictive ability was assessed using a test set of 10 compounds. The predictive 3D-QSAR models have conventional r2 values of 0.849 and 0.766 for MFA and RSA, respectively; while the cross-validated coefficient rcv2 values of 0.616 and 0.605 for MFA and RSA, respectively. The results of the QSAR model were further compared with a structure-based analysis using docking studies with crystal structure of JNK3. Ligands bind in the ATP pocket and the hydrogen bond with GLN155 was found to be crucial for selectivity among other kinases. The results of 3D-QSAR and docking studies validate each other and hence, the combination of both methodologies provides a powerful tool directed to the design of novel and selective JNK3 inhibitors.
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U2 - 10.1016/j.bmcl.2006.06.039
DO - 10.1016/j.bmcl.2006.06.039
M3 - Article
C2 - 16989998
AN - SCOPUS:33749250002
VL - 16
SP - 5917
EP - 5925
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 22
ER -