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.
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 r(cv)2 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.
Shaikh
Abdul Rajjak
AR
Department of Applied Chemistry, Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Sendai 980-8579, Japan.
Ismael
Mohamed
M
Del Carpio
Carlos A
CA
Tsuboi
Hideyuki
H
Koyama
Michihisa
M
Endou
Akira
A
Kubo
Momoji
M
Broclawik
Ewa
E
Miyamoto
Akira
A
D000097:Acetonitriles / Q000138:chemical synthesis / Q000494:pharmacology*; D000465:Algorithms; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006860:Hydrogen Bonding; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship
D000097:Acetonitriles; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D048057:Mitogen-Activated Protein Kinase 10