Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM–GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.

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Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies

Acta Pharmaceutica ◽

10.2478/acph-2021-0016 ◽

2021 ◽

Vol 71 (2) ◽

pp. 163-174

Author(s):

Safa Daoud ◽

Shada J. Alabed ◽

Lina A. Dahabiyeh

Keyword(s):

Binding Site ◽

Protease Inhibitors ◽

Specific Binding ◽

Antiviral Drug ◽

Pharmacophore Model ◽

Docking Study ◽

Pharmacophore Modeling ◽

Antiviral Drugs ◽

Crystallographic Structure ◽

Main Protease

AbstractThe current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today’s diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.

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Molecular dynamics simulation of docking structures of SARS-CoV-2 main protease and HIV protease inhibitors

Journal of Molecular Structure ◽

10.1016/j.molstruc.2020.129143 ◽

2021 ◽

Vol 1225 ◽

pp. 129143 ◽

Cited By ~ 4

Author(s):

Wesley B. Cardoso ◽

Sebastião A. Mendanha

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Protease Inhibitors ◽

Hiv Protease ◽

Dynamics Simulation ◽

Hiv Protease Inhibitors ◽

Main Protease

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Putative Inhibitors of SARS-CoV-2 Main Protease from A Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study

Marine Drugs ◽

10.3390/md18040225 ◽

2020 ◽

Vol 18 (4) ◽

pp. 225 ◽

Cited By ~ 56

Author(s):

Davide Gentile ◽

Vincenzo Patamia ◽

Angela Scala ◽

Maria Teresa Sciortino ◽

Anna Piperno ◽

...

Keyword(s):

Molecular Dynamics ◽

Severe Acute Respiratory Syndrome ◽

Middle Eastern ◽

Pharmacophore Model ◽

Hiv Protease ◽

Marine Natural Product ◽

Computational Techniques ◽

Hiv Protease Inhibitors ◽

Global Public Health ◽

Main Protease

The current emergency due to the worldwide spread of the COVID-19 caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness has not yet been assessed. The main protease (Mpro) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpro inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by a hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed this study to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpro inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.

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Inhibitors of SARS-CoV-2 Main Protease from a Library of Marine Natural Products: A Virtual Screening and Molecular Modeling Study

10.20944/preprints202003.0372.v1 ◽

2020 ◽

Cited By ~ 2

Author(s):

Davide Gentile ◽

Vincenzo Patamia ◽

Angela Scala ◽

Maria Teresa Sciortino ◽

Anna Piperno ◽

...

Keyword(s):

Molecular Dynamics ◽

Middle Eastern ◽

Pharmacophore Model ◽

Antiviral Agent ◽

Hiv Protease ◽

Marine Natural Product ◽

Computational Techniques ◽

Hiv Protease Inhibitors ◽

Global Public Health ◽

Main Protease

The current emergency due to the worldwide spread of the COVID-19 caused by the new SARS-CoV-2 is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness was not yet assessed. The main protease (Mpro) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpro inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpro inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.

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Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

10.21203/rs.3.rs-40776/v1 ◽

2020 ◽

Author(s):

mohamed mahdi ◽

János András Mótyán ◽

Zsófia Ilona Szojka ◽

Mária Golda ◽

Márió Miczi ◽

...

Keyword(s):

Cell Culture ◽

Protease Inhibitors ◽

Significant Inhibition ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

High Concentration ◽

Viral Protease ◽

Main Protease ◽

Depth Analysis

Abstract Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. Atazanavir on the other hand was the only PI to inhibit the viral protease both in cell culture and in our in vitro enzymatic assay. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

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Faculty Opinions recommendation of Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2's main protease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739120524.793580717 ◽

2020 ◽

Author(s):

Benoit Coulombe

Keyword(s):

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Main Protease

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Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2′s main protease

Virology Journal ◽

10.1186/s12985-020-01457-0 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Mohamed Mahdi ◽

János András Mótyán ◽

Zsófia Ilona Szojka ◽

Mária Golda ◽

Márió Miczi ◽

...

Keyword(s):

Cell Culture ◽

Protease Inhibitors ◽

Significant Inhibition ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Viral Protease ◽

Enzymatic Assays ◽

Main Protease ◽

Depth Analysis

Abstract Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. None of the inhibitors showed significant inhibition of SARS-CoV-2 Mpro in our in vitro enzymatic assays up to 100 µM concentration. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

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Analysis of the efficacy of HIV protease inhibitors against SARS-CoV-2’s main protease

10.21203/rs.3.rs-40776/v2 ◽

2020 ◽

Author(s):

mohamed mahdi ◽

János András Mótyán ◽

Zsófia Ilona Szojka ◽

Mária Golda ◽

Márió Miczi ◽

...

Keyword(s):

Cell Culture ◽

Protease Inhibitors ◽

Significant Inhibition ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Viral Protease ◽

Enzymatic Assays ◽

Main Protease ◽

Depth Analysis

Abstract BackgroundThe pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. MethodsWe carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed.ResultsLopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. None of the inhibitors showed significant inhibition of SARS-CoV-2 Mpro in our in vitro enzymatic assays up to 100 µM concentration. ConclusionTargeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.

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