Binding Free Energy Contributions of Interfacial Waters in HIV-1 Protease/Inhibitor Complexes

2006 ◽  
Vol 128 (36) ◽  
pp. 11830-11839 ◽  
Author(s):  
Yipin Lu ◽  
Chao-Yie Yang ◽  
Shaomeng Wang
Keyword(s):  
Free Energy ◽  
Protease Inhibitor ◽  
Binding Free Energy ◽  
Hiv 1

Accurate Ensemble Molecular Dynamics Binding Free Energy Ranking of Multidrug-Resistant HIV-1 Proteases

2010 ◽  
Vol 50 (5) ◽  
pp. 890-905 ◽  
Author(s):  
S. Kashif Sadiq ◽  
David W. Wright ◽  
Owain A. Kenway ◽  
Peter V. Coveney
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Multidrug Resistant ◽  
Hiv 1

Binding Free Energy Calculations of Nine FDA-approved Protease Inhibitors Against HIV-1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

2016 ◽  
Vol 87 (4) ◽  
pp. 487-498 ◽  
Author(s):  
Husain A. Lockhat ◽  
José R. A. Silva ◽  
Cláudio N. Alves ◽  
Thavendran Govender ◽  
Jerônimo Lameira ◽  
...  
Keyword(s):  
Amino Acids ◽  
Free Energy ◽  
Protease Inhibitors ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Subtype C ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Hiv 1

scholarly journals Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Son Tung Ngo ◽  
Ngoc Quynh Anh Pham ◽  
Ly Le ◽  
Duc-Hung Pham ◽  
Van Vu
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Targets ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Main Protease ◽  
Energy Perturbation ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Hiv 1

<p>The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1<sup>st</sup>, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, <i>cannabisin </i>A and <i>isoacteoside</i>, and an HIV-1 PR inhibitor, <i>darunavir</i>, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of <b>13b</b>, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of <i>darunavir </i>to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2. </p>

scholarly journals Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

2020 ◽  
Author(s):  
Ancy Iruthayaraj ◽  
Sivanandam Magudeeswaran ◽  
Kumaradhas Poomani
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Free Energy ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Mechanism ◽  
Main Protease ◽  
Repurposed Drugs ◽  
Hiv 1

<p>Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (M<sup>pro</sup>). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 M<sup>pro</sup>. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of M<sup>pro</sup> enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of M<sup>pro</sup> and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This <i>in silico</i> study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 M<sup>pro</sup> enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.</p>

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