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>

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>

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 Identification of promising drug candidates against Non-Structural Protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing studies

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Ekampreet Singh ◽  
Monika Jain ◽  
Gizachew Muluneh Amera ◽  
...  
Keyword(s):  
Free Energy ◽  
In Silico ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Therapeutic Agents ◽  
Global Dynamics ◽  
Host Immune System ◽  
Structural Protein ◽  
Drug Candidates

<div>The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The notorious nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an <i>in silico</i> based drug repurposing approach to identify potential drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2</div><div>which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. NSP15 was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated free energy of binding (<i>ΔG</i>), estimated inhibition constant (<i>Ki</i>), the orientation of drug molecules in the active site and the key interacting residues of</div><div>NSP15. The MD simulations were performed for the selected NSP15-drug complexes along with free protein to mimic on their physiological state. The binding free energies of the selected NSP15-drug complexes were also calculated using the trajectories of MD simulations of NSP15-drug complexes through MM/PBSA (Molecular Mechanics with Poisson-Boltzmann and surface area solvation) approach where NSP15-Simeprevir (-242.559 kJ/mol) and NSP15-Paritaprevir (-149.557 kJ/mol) exhibited the strongest binding affinities. Together with the results of molecular docking, global dynamics, essential dynamics and binding free energy analysis, we propose that Simeprevir and Paritaprevir are promising drug candidates for the inhibition of NSP15 and could act as potential therapeutic agents against SARS-CoV-2.</div>

scholarly journals Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Dileep Francis ◽  
Sadasivan C
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Target ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Energy Calculation ◽  
Viral Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

scholarly journals Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

2020 ◽  
Vol 117 (44) ◽  
pp. 27381-27387 ◽  
Author(s):  
Zhe Li ◽  
Xin Li ◽  
Yi-You Huang ◽  
Yaoxing Wu ◽  
Runduo Liu ◽  
...  
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Free Energy Perturbation ◽  
Therapeutic Effects ◽  
Screening Approach ◽  
Main Protease ◽  
Energy Perturbation ◽  
Virtual Screening Approach

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE−based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (inhibitory constant Ki= 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki= 0.36 µM) and chloroquine (Ki= 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.

scholarly journals Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

2020 ◽  
Author(s):  
Zhe Li ◽  
Xin Li ◽  
Yi-You Huang ◽  
Yaoxing Wu ◽  
Runduo Liu ◽  
...  
Keyword(s):  
Free Energy ◽  
Virtual Screening ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Free Energy Perturbation ◽  
Hit Rate ◽  
Screening Approach ◽  
Main Protease ◽  
Energy Perturbation ◽  
Virtual Screening Approach

AbstractCoronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and, thus, repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a new restraint energy distribution (RED) function designed to accelerate the FEP-ABFE calculations and make the practical FEP-ABFE-based virtual screening of the existing drug library possible for the first time. As a result, out of twenty-five drugs predicted, fifteen were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (Ki=0.04 μM) which has showed promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki=0.36 μM) and chloroquine (Ki=0.56 μM) were also found to potently inhibit SARS-CoV-2 Mpro for the first time. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.Significance StatementDrug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. It has been demonstrated that a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions can reach an unprecedently high hit rate, leading to successful identification of 16 potent inhibitors of SARS-CoV-2 main protease (Mpro) from computationally selected 25 drugs under a threshold of Ki = 4 μM. The outcomes of this study are valuable for not only drug repurposing to treat COVID-19, but also demonstrating the promising potential of the FEP-ABFE prediction-based virtual screening approach.

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 Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Dileep Francis ◽  
Sadasivan C
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Target ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Energy Calculation ◽  
Viral Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

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