Next Article in Journal
Huge Inverse Magnetization Generated by Faraday Induction in Nano-Sized [email protected] [email protected] Nanoparticles
Previous Article in Journal
AGEs-Induced IL-6 Synthesis Precedes RAGE Up-Regulation in HEK 293 Cells: An Alternative Inflammatory Mechanism?
Previous Article in Special Issue
Double Variational Binding—(SMILES) Conformational Analysis by Docking Mechanisms for Anti-HIV Pyrimidine Ligands
Article Menu
Issue 9 (September) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2015, 16(9), 20118-20138;

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations

Lab of Systems Pharmacology, College of Life Sciences, Northwest A&F (Agriculture and Forestry) University, Yangling 712100, China
Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences, Dalian 116023, China
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editor: Jesus Vicente De Julián Ortiz
Received: 28 May 2015 / Revised: 10 July 2015 / Accepted: 30 July 2015 / Published: 25 August 2015
(This article belongs to the Special Issue Chemical Bond and Bonding 2015)
Full-Text   |   PDF [3580 KB, uploaded 26 August 2015]   |  


Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q2 (cross-validated correlation coefficient) = 0.557, R2ncv (non-cross-validated correlation coefficient) = 0.740, R2pre (predicted correlation coefficient) = 0.749 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors. View Full-Text
Keywords: imidazoles; TNF-α; inhibitor; 3D-QSAR; CoMFA; CoMSIA; DISCOtech; pharmacophore imidazoles; TNF-α; inhibitor; 3D-QSAR; CoMFA; CoMSIA; DISCOtech; pharmacophore

Figure 1

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 (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

Wang, Y.; Wu, M.; Ai, C.; Wang, Y. Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations. Int. J. Mol. Sci. 2015, 16, 20118-20138.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics



[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