Next Article in Journal
High Mitochondrial DNA Copy Number and Bioenergetic Function Are Associated with Tumor Invasion of Esophageal Squamous Cell Carcinoma Cell Lines
Previous Article in Journal
Synthesis and Antimicrobial Activity of Some Novel Cross-Linked Chitosan Hydrogels
Article Menu

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2012, 13(9), 11210-11227; doi:10.3390/ijms130911210

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

Key Lab of Tianjin Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin 300192, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 27 June 2012 / Revised: 16 July 2012 / Accepted: 30 July 2012 / Published: 10 September 2012
(This article belongs to the Section Physical Chemistry, Theoretical and Computational Chemistry)

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. View Full-Text
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 (CC BY 3.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

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.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top