Integrated Computational Tools for Identification of CCR5 Antagonists as Potential HIV-1 Entry Inhibitors: Homology Modeling, Virtual Screening, Molecular Dynamics Simulations and 3D QSAR Analysis

Molecules

Suri Moonsamy¹  Radha Charan Dash¹ 

[1] id="af1-molecules-19-05243">School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Afric

关键词: CCR5 antagonists;    HIV-1 entry inhibitors;    homology modeling;    virtual screening;    molecular dynamic simulations;    3D QSAR analysis;    computer-aided drug design;   

DOI  :  10.3390/molecules19045243

来源: mdpi

【 摘 要 】

Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed that novel leads demonstrated better binding affinities with CCR5 compared to maraviroc, an FDA-approved HIV-1 entry inhibitor and in clinical use. Per-residue interaction energy decomposition analysis on the averaged MD structure showed that hydrophobic active residues Trp86, Tyr89 and Tyr108 contributed the most to inhibitor binding. The validated 3D-QSAR model showed a high cross-validated r_cv² value of 0.84 using three principal components and non-cross-validated r² value of 0.941. It was also revealed that almost all compounds in the test set and training set yielded a good predicted value. Information gained from this study could shed light on the activity of a new series of lead compounds as potential HIV entry inhibitors and serve as a powerful tool in the drug design and development machinery.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.