scholarly journals Development of Potential HIV-1 Inhibitors by In Silico Click Chemistry And Molecular Modeling Methods

2018 ◽  
Vol 13 (2) ◽  
pp. 507-525 ◽  
Author(s):  
A.M. Andrianov ◽  
G.I. Nikolaev ◽  
I.A. Kashyn ◽  
A.V. Tuzikov
Keyword(s):  
Molecular Modeling ◽  
Click Chemistry ◽  
In Silico ◽  
Viral Neutralization ◽  
Drug Candidates ◽  
Modular Units ◽  
Gp120 Protein ◽  
Cd4 Binding Site ◽  
Hiv Drugs ◽  
Hiv 1

Design of novel potential HIV-1 inhibitors able to block CD4-binding site of the envelope gp120 protein was carried out based on click chemistryin silico, a methodology allowing one to generate a large number of drug candidates by assembly from small modular units and to study their properties. Using the methods of molecular modeling, the neutralizing activity of designed molecules was evaluated, as a result of which five leading compounds that are promising for synthesis and biological trials were identified. Their chemical formulas are C24H23N7O2, C23H20N6O2, C21H17F3N6, C22H20ClN9O and C19H15N9O. It has been shown that these compounds can be used as good scaffolds for the development of novel potent and broad anti-HIV drugs with extensive viral neutralization effect.

In silico search, chemical characterization and immunogenic evaluation of amino-terminated G4-PAMAM-HIV peptide complexes using three-dimensional models of the HIV-1 gp120 protein

2019 ◽  
Vol 177 ◽  
pp. 77-93 ◽  
Author(s):  
Rolando Alberto Rodríguez-Fonseca ◽  
Martiniano Bello ◽  
María Ángeles de los Muñoz-Fernández ◽  
José Luis Jiménez ◽  
Saúl Rojas-Hernández ◽  
...  
Keyword(s):  
In Silico ◽  
Three Dimensional ◽  
Chemical Characterization ◽  
Gp120 Protein ◽  
Peptide Complexes ◽  
Dimensional Models ◽  
Three Dimensional Models ◽  
Hiv 1

scholarly journals In silico Identification of High-Affinity Ligands of the Hiv-1 Gp120 Protein, Potential Peptidomimetics of Neutralizing Antibody N6

2019 ◽  
Vol 14 (2) ◽  
pp. 430-449 ◽  
Author(s):  
A.M. Andrianov ◽  
G.I. Nikolaev ◽  
Y.V. Kornoushenko ◽  
J. Huang ◽  
S. Jiang ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Experimental Studies ◽  
Neutralizing Antibody ◽  
Positive Control ◽  
Effective Interactions ◽  
Affinity Ligands ◽  
Gp120 Protein ◽  
Cd4 Binding Site ◽  
Anti Hiv ◽  
Hiv 1

Six potential peptidomimetics of the cross-reactive neutralizing anti-HIV-1 antibody N6 that are able to mimic the pharmacophoric features of this immunoglobulin by specific and effective interactions with the CD4-binding site of the viral gp120 protein were identified by virtual screening and molecular modeling. The key role in the interaction of these compounds with gp120 is shown to play multiple van der Waals contacts with conserved residues of the gp120 Phe-43 cavity critical for the HIV binding to cellular receptor CD4, as well as hydrogen bond with Asp-368gp120 that increase the chemical affinity without activating unwanted allosteric effect. According to the data of molecular dynamics, the complexes of the identified ligands with gp120 are energetically stable and show the lower values of binding free energy compared with the HIV-1 inhibitors NBD-11021 and DMJ-II-121 used in the calculations as a positive control. Based on the data obtained, it was concluded that the identified compounds may be considered as promising candidates for detailed experimental studies to their further use in the design of novel antiviral drugs presenting HIV-1 inhibitors that block the early stages of the development of HIV infection.

scholarly journals Design and Identification of Potential HIV-1 Entry Inhibitors Using In Silico Click Chemistry and Molecular Modeling Methods

2021 ◽  
Vol 16 (2) ◽  
pp. 317-334
Author(s):  
A.M. Andrianov ◽  
A.M. Yushkevich ◽  
I.P. Bosko ◽  
A.D. Karpenko ◽  
Yu.V. Kornoushenko ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Click Chemistry ◽  
Computer Aided Design ◽  
Integrated Approach ◽  
Viral Envelope ◽  
Entry Inhibitors ◽  
Fusion Inhibitors ◽  
Host Cell Membranes ◽  
Aided Design ◽  
Hiv 1

An integrated approach including the click chemistry methodology, molecular docking, quantum mechanics, and molecular dynamics was used to computer-aided design of potential HIV-1 inhibitors able to block the membrane-proximal external region (MPER) of HIV-1 gp41, which plays an important role in the fusion of the viral and host cell membranes. Evaluation of the binding efficiency of the designed compounds to the HIV-1 MPER peptide was performed using the methods of molecular modeling, resulting in nine chemical compounds exhibiting high-affinity binding to this functionally important site of the trimeric “spike” of the viral envelope. The data obtained indicate that the identified compounds are promising for the development of novel antiviral drugs, HIV fusion inhibitors blocking the early stages of HIV infection.

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

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.

scholarly journals Click chemistry and molecular modeling methods in computer-aided design and identification of potential HIV-1 inhibitors

2021 ◽  
Vol 65 (6) ◽  
pp. 680-691
Author(s):  
A. M. Andrianov ◽  
A. M. Yushkevich ◽  
I. P. Bosko ◽  
A. D. Karpenko ◽  
Yu. V. Kornoushenko ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Click Chemistry ◽  
Computer Aided Design ◽  
Integrated Approach ◽  
Viral Envelope ◽  
Fusion Inhibitors ◽  
Computer Aided ◽  
Host Cell Membranes ◽  
Aided Design ◽  
Hiv 1

An integrated approach including the click chemistry methodology, molecular docking, quantum mechanics, and molecular dynamics was used to perform the computer-aided design of potential HIV-1 inhibitors able to block the membrane- proximal external region (MPER) of HIV-1 gp41 that plays an important role in the fusion of the viral and host cell membranes. Evaluation of the binding efficiency of the designed compounds to the HIV-1 MPER peptide was performed using the methods of molecular modeling, resulting in nine chemical compounds that exhibit the high-affinity binding to this functionally important site of the trimeric “spike” of the viral envelope. The data obtained indicate that the identified compounds are promising for the development of novel antiviral drugs, HIV fusion inhibitors blocking the early stages of HIV infection.

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

Viruses ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 746 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Grigory I. Nikolaev ◽  
Yuri V. Kornoushenko ◽  
Wei Xu ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Cellular Receptor ◽  
Dynamic Simulations ◽  
Entry Inhibitors ◽  
Fusion Inhibitors ◽  
Gp120 Protein ◽  
Hiv 1

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.

Molecular Modeling Approaches for the Prediction of Selected Pharmacokinetic Properties

2019 ◽  
Vol 18 (26) ◽  
pp. 2230-2238 ◽  
Author(s):  
Emilio S. Petito ◽  
David J.R. Foster ◽  
Michael B. Ward ◽  
Matthew J. Sykes
Keyword(s):  
Molecular Modeling ◽  
In Silico ◽  
Volume Of Distribution ◽  
Future Directions ◽  
Unbound Fraction ◽  
Drug Candidates ◽  
New Methods ◽  
Pharmacokinetic Properties

Poor profiles of potential drug candidates, including pharmacokinetic properties, have been acknowledged as a significant hindrance to the development of modern therapeutics. Contemporary drug discovery and development would be incomplete without the aid of molecular modeling (in-silico) techniques, allowing the prediction of pharmacokinetic properties such as clearance, unbound fraction, volume of distribution and bioavailability. As with all models, in-silico approaches are subject to their interpretability, a trait that must be balanced with accuracy when considering the development of new methods. The best models will always require reliable data to inform them, presenting significant challenges, particularly when appropriate in-vitro or in-vivo data may be difficult or time-consuming to obtain. This article seeks to review some of the key in-silico techniques used to predict key pharmacokinetic properties and give commentary on the current and future directions of the field.

scholarly journals Virtual screening and identification of potential HIV-1 inhibitors based on the cross-reactive neutralizing antibody N6

2019 ◽  
Vol 63 (4) ◽  
pp. 445-456 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Gregory I. Nikolaev ◽  
Yuri V. Kornoushenko ◽  
Jinghe Huang ◽  
Shibo Jiang ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Free Energy ◽  
Neutralizing Antibody ◽  
Positive Control ◽  
Effective Interactions ◽  
Gp120 Protein ◽  
Cd4 Binding Site ◽  
Screening And Identification ◽  
The Cross ◽  
Hiv 1

Six potential peptidomimetics of the cross-reactive neutralizing anti-HIV-1 antibody N6 that are able to mimic the pharmacophoric features of this immunoglobulin by specific and effective interactions with the CD4-binding site of the viral gp120 protein were identified by virtual screening and molecular modeling. The key role in the interaction of these compounds with gp120 is shown to play multiple van der Waals contacts with conserved residues of the gp120 Phe43 cavity critical for the HIV binding to cellular receptor CD4, as well as hydrogen bonds with Asp-368gp120 that increase the chemical affinity without activating unwanted allosteric effect. According to the data of molecular dynamics, the complexes of the identified ligands with gp120 are energetically stable and show the lower values of binding free energy compared with the HIV-1 inhibitors NBD-11021 and DMJ-II-121 used in the calculations as a positive control. The identified compounds may be involved in the design of novel antiviral drugs presenting HIV-1 inhibitors that block the early stages of the development of HIV infection.

Flexibility of Important HIV-1 Targets and in silico Design of anti- HIV Drugs

2018 ◽  
Vol 12 (1) ◽  
pp. 23-39 ◽  
Author(s):  
Elvis A.F. Martis ◽  
Blessy Joseph ◽  
Satya P. Gupta ◽  
Evans C. Coutinho ◽  
Ismail Hdoufane ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Design ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1
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