A Combination of 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies of Benzimidazole-Quinolinone Derivatives as iNOS Inhibitors

International Journal of Molecular Sciences

Hao Zhang¹  Jinhang Zan¹  Guangyun Yu²  Ming Jiang² 

[1] Key Lab of Tianjin Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin 300192, China;

关键词: 3D-QSAR;    benzimidazole-quinolinone derivatives;    molecular dynamics simulation;    molecular docking;    iNOS inhibitor;   

DOI  :  10.3390/ijms130911210

来源: mdpi

【 摘 要 】

Inducible Nitric Oxide Synthase (iNOS) has been involved in a variety of diseases, and thus it is interesting to discover and optimize new iNOS inhibitors. In previous studies, a series of benzimidazole-quinolinone derivatives with high inhibitory activity against human iNOS were discovered. In this work, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking and molecular dynamics (MD) simulation approaches were applied to investigate the functionalities of active molecular interaction between these active ligands and iNOS. A QSAR model with R² of 0.9356, Q² of 0.8373 and Pearson-R value of 0.9406 was constructed, which presents a good predictive ability in both internal and external validation. Furthermore, a combined analysis incorporating the obtained model and the MD results indicates: (1) compounds with the proper-size hydrophobic substituents at position 3 in ring-C (R₃ substituent), hydrophilic substituents near the X₆ of ring-D and hydrophilic or H-bond acceptor groups at position 2 in ring-B show enhanced biological activities; (2) Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485 are key amino acids in the active pocket, and activities of iNOS inhibitors are consistent with their capability to alter the position of these important residues, especially Glu371 and Thr370. The results provide a set of useful guidelines for the rational design of novel iNOS inhibitors.

【 授权许可】

CC BY   
© 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.