The mystery of chemistry behind the mechanism of action of anti-HIV drugs: A docking approach at an atomic level

The effect of HIV-1 on a human’s immune system cannot be ignored. This is the virus that reduces the power of the immune system to fight against any disease. Of course, many anti-HIV drugs are available, and many computational studies have been done to find out their mechanism of action, but the computational study regarding the chemistry behind the mechanism of action was not done yet. Therefore, the main objective of the study was to clarify the chemistry behind the mechanism of action of commercially available anti-HIV drugs. The drugs taken in the presented study were Entry Inhibitors (EIs) and Non-nucleoside reverse transcriptase inhibitors. First, literature data was evaluated computationally to ensure the reliability of the software used for the presented study. It was found that interaction-based experimental results and computationally evaluated results of the literature data were the same. After that, by following the same procedure, a docking study was done on the drugs taken in the current study. In addition, the residues involved in the interactions of EIs and NNRTIs with their receptors were studied to determine the chemistry that acts behind the action of both. It was found that EIs and NNRTIs work differently. It was also predicted that the derivatization of both drugs could make them more effective and active. Therefore, the presented study will be very helpful in the field of medicinal science.

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Potent Synergistic Anti-Human Immunodeficiency Virus (HIV) Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01299-07 ◽

2008 ◽

Vol 52 (6) ◽

pp. 2111-2119 ◽

Cited By ~ 18

Author(s):

Hirotomo Nakata ◽

Seth M. Steinberg ◽

Yasuhiro Koh ◽

Kenji Maeda ◽

Yoshikazu Takaoka ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Synergistic Effects ◽

Immunodeficiency Virus ◽

Approved Drugs ◽

Hiv Drugs ◽

Nonparametric Statistical ◽

Anti Hiv ◽

Ccr5 Inhibitor ◽

Hiv 1

ABSTRACT Aplaviroc (AVC), an experimental CCR5 inhibitor, potently blocks in vitro the infection of R5-tropic human immunodeficiency virus type 1 (R5-HIV-1) at subnanomolar 50% inhibitory concentrations. Although maraviroc is presently clinically available, further studies are required to determine the role of CCR5 inhibitors in combinations with other drugs. Here we determined anti-HIV-1 activity using combinations of AVC with various anti-HIV-1 agents, including four U.S. Food and Drug Administration-approved drugs, two CCR5 inhibitors (TAK779 and SCH-C) and two CXCR4 inhibitors (AMD3100 and TE14011). Combination effects were defined as synergistic or antagonistic when the activity of drug A combined with B was statistically greater or less, respectively, than the additive effects of drugs A and A combined and drugs B and B combined by using the Combo method, described in this paper, which provides (i) a flexible choice of interaction models and (ii) the use of nonparametric statistical methods. Synergistic effects against R5-HIV-1Ba-L and a 50:50 mixture of R5-HIV-1Ba-L and X4-HIV-1ERS104pre (HIV-1Ba-L/104pre) were seen when AVC was combined with zidovudine, nevirapine, indinavir, or enfuvirtide. Mild synergism and additivity were observed when AVC was combined with TAK779 and SCH-C, respectively. We also observed more potent synergism against HIV-1Ba-L/104pre when AVC was combined with AMD3100 or TE14011. The data demonstrate a tendency toward greater synergism with AVC plus either of the two CXCR4 inhibitors compared to the synergism obtained with combinations of AVC and other drugs, suggesting that the development of effective CXCR4 inhibitors may be important for increasing the efficacies of CCR5 inhibitors.

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Sensitivity of V75I HIV-1 reverse transcriptase mutant selected in vitro by acyclovir to anti-HIV drugs

AIDS ◽

10.1097/qad.0b013e32833424e5 ◽

2010 ◽

Vol 24 (2) ◽

pp. 319-323 ◽

Cited By ~ 2

Author(s):

Moira A McMahon ◽

Janet D Siliciano ◽

Rahul M Kohli ◽

Robert F Siliciano

Keyword(s):

Reverse Transcriptase ◽

Hiv Drugs ◽

Anti Hiv ◽

Hiv 1

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Betulinic Acid Derivatives That Target gp120 and Inhibit Multiple Genetic Subtypes of Human Immunodeficiency Virus Type 1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00737-07 ◽

2007 ◽

Vol 52 (1) ◽

pp. 128-136 ◽

Cited By ~ 27

Author(s):

Weihong Lai ◽

Li Huang ◽

Phong Ho ◽

Zhijun Li ◽

David Montefiori ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Broad Spectrum ◽

Betulinic Acid ◽

V3 Loop ◽

Entry Inhibitors ◽

Immunodeficiency Virus ◽

Anti Hiv ◽

Hiv 1

ABSTRACT Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors. IC9564 was especially potent in increasing the sensitivity of HIV-1YU2 Env-mediated membrane fusion to the CCR5 inhibitor TAK-779. Results from this study suggest that the V3 loop of gp120 is a critical determinant for the anti-HIV-1 activity of IC9564. IC9564 escape viruses contained mutations near the tip of the V3 loop. Moreover, IC9564 could compete with the binding of V3 monoclonal antibodies 447-52D and 39F. IC9564 also competed with the binding of gp120/CD4 complexes to chemokine receptors. In summary, these results suggest that BA entry inhibitors can potently inhibit a broad spectrum of primary HIV-1 isolates by targeting the V3 loop of gp120.

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2-Aminothiazolones as Anti-HIV Agents That Act as gp120-CD4 Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02739-13 ◽

2014 ◽

Vol 58 (6) ◽

pp. 3043-3052 ◽

Cited By ~ 10

Author(s):

Marika Tiberi ◽

Cristina Tintori ◽

Elisa Rita Ceresola ◽

Roberta Fazi ◽

Claudio Zamperini ◽

...

Keyword(s):

Early Stage ◽

Biological Properties ◽

Docking Simulations ◽

Protein Protein Interaction ◽

Entry Inhibitors ◽

Antiviral Activities ◽

Hiv Entry ◽

Anti Hiv Agents ◽

Anti Hiv ◽

Hiv 1

ABSTRACTWe report here the synthesis of 2-aminothiazolones along with their biological properties as novel anti-HIV agents. Such compounds have proven to act through the inhibition of the gp120-CD4 protein-protein interaction that occurs at the very early stage of the HIV-1 entry process. No cytotoxicity was found for these compounds, and broad antiviral activities against laboratory strains and pseudotyped viruses were documented. Docking simulations have also been applied to predict the mechanism, at the molecular level, by which the inhibitors were able to interact within the Phe43 cavity of HIV-1 gp120. Furthermore, a preliminary absorption, distribution, metabolism, and excretion (ADME) evaluation was performed. Overall, this study led the basis for the development of more potent HIV entry inhibitors.

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Anti-HIV-1 Integrase Activity and Molecular Docking Study of Compounds from Caesalpinia sappan L.

Phytotherapy Research ◽

10.1002/ptr.5307 ◽

2015 ◽

Vol 29 (5) ◽

pp. 724-729 ◽

Cited By ~ 9

Author(s):

Supinya Tewtrakul ◽

Prapaporn Chaniad ◽

Somsak Pianwanit ◽

Chatchanok Karalai ◽

Chanita Ponglimanont ◽

...

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Molecular Docking Study ◽

Caesalpinia Sappan ◽

Anti Hiv ◽

Hiv 1

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Predicting binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase using molecular docking

Science and Technology Development Journal - Natural Sciences ◽

10.32508/stdjns.v2i1.674 ◽

2019 ◽

Vol 2 (1) ◽

pp. 53-58

Author(s):

Nguyen Truong Tien ◽

Bui Tho Thanh

Keyword(s):

Molecular Docking ◽

Reverse Transcriptase ◽

Binding Pocket ◽

The Body ◽

Binding Modes ◽

Weakly Bound ◽

Hiv Drugs ◽

Anti Hiv ◽

Hiv 1 ◽

Hiv Aids

The HIV/AIDS epidemic has become one of the most dangerous causes leading to millions of deaths around the world a year. To date, there have not had effective anti-HIV drugs in the treatment of HIV/AIDS because of emerging drug-resistant HIV mutants. In this work, potential non-nucleoside reverse transcriptase inhibitors (NNRTIs) were studied by means of molecular docking. The Diversity “drug-like” database from the National Cancer Institute, is composed of 1.420 compounds, was performed docking into the NNRTI binding pocket of HIV-1 reverse transcriptase crystal structure (1fk9) by using Autodock version 4.2.6. Pharmacokinetic properties (absorption, distribution, metabolism and excretion (ADME)) and toxicity of potential inhibitors within the body were predicted by the PreADMET version 2.0. The obtained results point out that the compound, coded 2518, was discovered as a potential inhibitor that has good human intestinal absorption, weakly bound to plasma proteins as well as is negative to mutagenicity and carcinogenicity. This rational inhibitor would be further studied in order to contribute informations finding new anti-HIV drugs.

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Molecular dynamics for structural complexes of potential HIV-1 inhibitors with the viral envelope gp120 protein

Doklady of the National Academy of Sciences of Belarus ◽

10.29235/1561-8323-2018-62-5-576-584 ◽

2018 ◽

Vol 62 (5) ◽

pp. 576-584

Author(s):

I. A. Kashyn ◽

G. I. Nikolaev ◽

M. A. Tuzikov ◽

A. M. Andrianov

Keyword(s):

Molecular Dynamics ◽

Viral Envelope ◽

Amino Acid Residues ◽

Free Energies ◽

Gp120 Protein ◽

Dynamics Simulations ◽

Hiv Drugs ◽

Anti Hiv ◽

Hiv 1 ◽

Envelope Gp120

Molecular dynamics simulations for the structural complexes of potential HIV-1 inhibitors with the viral envelope gp120 protein were carried out. Free energies of the formation of these supramolecular structures and contributions of individual amino-acid residues of gp120 to the enthalpy binding were calculated. The residues of gp120 critical for interactions with the ligands were identified. Based on the data obtained, five compounds promising for synthesis and testing for antiviral activity were selected. It is suggested that these compounds may be successfully used in the design of novel, potent and broad anti-HIV drugs.

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Discovery, SAR study and ADME properties of methyl 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1H-pyrazole-5-carboxylate as an HIV-1 replication inhibitor

RSC Medicinal Chemistry ◽

10.1039/d0md00025f ◽

2020 ◽

Vol 11 (5) ◽

pp. 577-582

Author(s):

Jeanne Fichez ◽

Cathia Soulie ◽

Laurent Le Corre ◽

Sophie Sayon ◽

Stéphane Priet ◽

...

Keyword(s):

Viral Resistance ◽

Adme Properties ◽

Replication Inhibitor ◽

Hiv Drugs ◽

Sar Study ◽

Anti Hiv ◽

Hiv 1

Identified as an HIV-1 inhibitor in cellulo, this pyrazole does not belong to the three main classes of anti HIV-drugs, a feature of prime interest in the context of viral resistance.

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