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.
Highlights
Human immunodeficiency virus type 1 (HIV-1) that was first identified in 1983 is the direct cause of the development of acquired immunodeficiency syndrome (AIDS) [1]
Despite significant 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
The choice of aromatic molecules as modular units for the design of CD4-mimetic candidates is due to the fact that their aromatic moieties can mimic the key interactions of Phe-43CD4 with the Phe-43 cavity of gp120 that dominate the HIV-1 binding to CD4
Summary
Human immunodeficiency virus type 1 (HIV-1) that was first identified in 1983 is the direct cause of the development of acquired immunodeficiency syndrome (AIDS) [1]. As of July 2018, the number of HIV-infected patients in the world was approximately 37 million people, with the majority of HIV infections in Asia, Africa and South America [2]. The higher incidence and prevalence of HIV infection in these countries does not reduce the relevance of the problem of HIV/AIDS for the states of North. As of 2015, the pace of the development of the HIV pandemic in the world has declined, this problem still requires an urgent solution [2]. More than 25 drugs have been approved for clinical use by the USA food and drug administration [3]. Depending on the mechanism of action, these drugs are divided into classes including reverse transcriptase inhibitors, proteases, integrases and entry/fusion inhibitors [3,4,5,6,7,8]
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