Next Article in Journal
Alkyl-Substituted δ-Lactones Derived from Dihydrojasmone and Their Stereoselective Fungi-Mediated Conversion: Production of New Antifeedant Agents
Next Article in Special Issue
Molecular Docking Optimization in the Context of Multi-Drug Resistant and Sensitive EGFR Mutants
Previous Article in Journal
Synergistic Antipseudomonal Effects of Synthetic Peptide AMP38 and Carbapenems
Previous Article in Special Issue
Predicting Protein-Protein Interactions Using BiGGER: Case Studies
Article Menu
Issue 9 (September) cover image

Export Article

Open AccessArticle
Molecules 2016, 21(9), 1222; doi:10.3390/molecules21091222

Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations

1
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China
2
The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
*
Author to whom correspondence should be addressed.
Academic Editor: Alessandro Pedretti
Received: 13 July 2016 / Revised: 21 August 2016 / Accepted: 9 September 2016 / Published: 19 September 2016
(This article belongs to the Collection Molecular Docking)
View Full-Text   |   Download PDF [4438 KB, uploaded 19 September 2016]   |  

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors. View Full-Text
Keywords: 11β-HSD1; 3D-QSAR; MESP; MD simulations; binding free energy 11β-HSD1; 3D-QSAR; MESP; MD simulations; binding free energy
Figures

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

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

Qian, H.; Chen, J.; Pan, Y.; Chen, J. Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations. Molecules 2016, 21, 1222.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top