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Molecules 2014, 19(4), 5243-5265; doi:10.3390/molecules19045243
Article

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

,  and *
Received: 27 January 2014; in revised form: 1 April 2014 / Accepted: 9 April 2014 / Published: 23 April 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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Abstract: 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 rcv2 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.
Keywords: CCR5 antagonists; HIV-1 entry inhibitors; homology modeling; virtual screening; molecular dynamic simulations; 3D QSAR analysis; computer-aided drug design CCR5 antagonists; HIV-1 entry inhibitors; homology modeling; virtual screening; molecular dynamic simulations; 3D QSAR analysis; computer-aided drug design
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.

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MDPI and ACS Style

Moonsamy, S.; Dash, R.C.; Soliman, M.E.S. 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 2014, 19, 5243-5265.

AMA Style

Moonsamy S, Dash RC, Soliman MES. 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. 2014; 19(4):5243-5265.

Chicago/Turabian Style

Moonsamy, Suri; Dash, Radha C.; Soliman, Mahmoud E.S. 2014. "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 19, no. 4: 5243-5265.


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