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

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 22; pp. 5917 - 5925
• Main Authors: Shaikh, Abdul Rajjak, Ismael, Mohamed, Del Carpio, Carlos A., Tsuboi, Hideyuki, Koyama, Michihisa, Endou, Akira, Kubo, Momoji, Broclawik, Ewa, Miyamoto, Akira
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.11.2006; Elsevier
• Subjects: 3D-QSAR; Acetonitriles - chemical synthesis; Acetonitriles - pharmacology; Algorithms; Analytical, structural and metabolic biochemistry; Benzothiazoles - chemical synthesis; Benzothiazoles - pharmacology; Binding Sites; Biological and medical sciences; c-Jun N-terminal kinase-3; Docking; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hydrogen Bonding; JNK3 inhibitors; Medical sciences; MFA; Miscellaneous; Mitogen-Activated Protein Kinase 10 - antagonists & inhibitors; Molecular Conformation; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; RSA; Transferases; 3D-QSAR; JNK3 inhibitors; RSA; c-Jun N-terminal kinase-3; MFA; Docking; Nitrogen heterocycle; Binding site; Selectivity; Modeling; Signal transduction; Structure activity relation; Molecular model; Bicyclic compound; Aromatic compound; Sulfur nitrogen heterocycle; Enzyme; Transferases; Prediction; Enzyme inhibitor; Mitogen-activated protein kinase; Inhibitor enzyme complex; Three dimensional model; Protein kinase; Pyrimidine derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.06.039

We have developed a 3D-QSAR model and performed a series of structural studies on a series of benzothiazole-2yl acetonitrile derivatives with high inhibition activity towards c-Jun N-terminal kinase-3. The results were compared with experimental structure-based studies using JNK3 crystal structure to gain insight into the structural requirements for inhibitory activity of this class. 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 r 2 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.