Next Article in Journal
Previous Article in Journal
Int. J. Mol. Sci. 2012, 13(9), 11210-11227; doi:10.3390/ijms130911210
Article

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

,
,
,
 and *
Received: 27 June 2012; in revised form: 16 July 2012 / Accepted: 30 July 2012 / Published: 10 September 2012
View Full-Text   |   Download PDF [4164 KB, updated 19 June 2014; original version uploaded 19 June 2014]
Abstract: 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.
Keywords: 3D-QSAR; benzimidazole-quinolinone derivatives; molecular dynamics simulation; molecular docking; iNOS inhibitor 3D-QSAR; benzimidazole-quinolinone derivatives; molecular dynamics simulation; molecular docking; iNOS inhibitor
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Export to BibTeX |
EndNote


MDPI and ACS Style

Zhang, H.; Zan, J.; Yu, G.; Jiang, M.; Liu, P. A Combination of 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies of Benzimidazole-Quinolinone Derivatives as iNOS Inhibitors. Int. J. Mol. Sci. 2012, 13, 11210-11227.

AMA Style

Zhang H, Zan J, Yu G, Jiang M, Liu P. A Combination of 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies of Benzimidazole-Quinolinone Derivatives as iNOS Inhibitors. International Journal of Molecular Sciences. 2012; 13(9):11210-11227.

Chicago/Turabian Style

Zhang, Hao; Zan, Jinhang; Yu, Guangyun; Jiang, Ming; Liu, Peixun. 2012. "A Combination of 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation Studies of Benzimidazole-Quinolinone Derivatives as iNOS Inhibitors." Int. J. Mol. Sci. 13, no. 9: 11210-11227.


Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert