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In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4

1
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141 Minsk, Belarus
2
United Institute of Informatics Problems, National Academy of Sciences of Belarus, 220012 Minsk, Belarus
3
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, 131 Dong An Road, Fuxing Building, Shanghai 200032, China
*
Authors to whom correspondence should be addressed.
Viruses 2019, 11(8), 746; https://doi.org/10.3390/v11080746
Received: 10 July 2019 / Revised: 31 July 2019 / Accepted: 1 August 2019 / Published: 13 August 2019
(This article belongs to the Special Issue Viral Entry Pathways)
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Abstract

Despite recent progress in the development of novel potent HIV-1 entry/fusion inhibitors, there are currently no licensed antiviral drugs based on inhibiting the critical interactions of the HIV-1 envelope gp120 protein with cellular receptor CD4. In this connection, studies on the design of new small-molecule compounds able to block the gp120-CD4 binding are still of great value. In this work, in silico design of drug-like compounds containing the moieties that make the ligand active towards gp120 was performed within the concept of click chemistry. Complexes of the designed molecules bound to gp120 were then generated by molecular docking and optimized using semiempirical quantum chemical method PM7. Finally, the binding affinity analysis of these ligand/gp120 complexes was performed by molecular dynamic simulations and binding free energy calculations. As a result, five top-ranking compounds that mimic the key interactions of CD4 with gp120 and show the high binding affinity were identified as the most promising CD4-mimemic candidates. Taken together, the data obtained suggest that these compounds may serve as promising scaffolds for the development of novel, highly potent and broad anti-HIV-1 therapeutics. View Full-Text
Keywords: HIV-1 gp120 protein; cellular receptor CD4; CD4-mimetics; virtual screening; in silico click chemistry; molecular docking; quantum chemical calculations; molecular dynamics simulations; binding free energy calculations; anti-HIV-1 drugs HIV-1 gp120 protein; cellular receptor CD4; CD4-mimetics; virtual screening; in silico click chemistry; molecular docking; quantum chemical calculations; molecular dynamics simulations; binding free energy calculations; anti-HIV-1 drugs
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Andrianov, A.M.; Nikolaev, G.I.; Kornoushenko, Y.V.; Xu, W.; Jiang, S.; Tuzikov, A.V. In Silico Identification of Novel Aromatic Compounds as Potential HIV-1 Entry Inhibitors Mimicking Cellular Receptor CD4. Viruses 2019, 11, 746.

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