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

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 225 ◽  
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.

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

2020 ◽  
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.

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

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7385
Author(s):  
Wei Yu ◽  
Xiaomin Wu ◽  
Yizhen Zhao ◽  
Chun Chen ◽  
Zhiwei Yang ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Computational Simulation ◽  
Antiviral Drug ◽  
Interaction Mechanism ◽  
Pharmacophore Model ◽  
Md Simulations ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hydrogen Bond Donor ◽  
Main Protease

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.

scholarly journals Antiviral therapy of COVID-19

2020 ◽  
Vol 51 (3) ◽  
pp. 131-133
Author(s):  
Slobodan Janković
Keyword(s):  
Clinical Trials ◽  
Severe Acute Respiratory Syndrome ◽  
Wide Spectrum ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Antiviral Action ◽  
Efficacy And Safety ◽  
Risks And Benefits ◽  
Nucleotide Analogue ◽  
Potential Risks

The COVID-19 pandemic required rapid response to the needs of critically ill patients, and one of the solutions was re-purposing of drugs with wide spectrum of antiviral action for treatment of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. The re-purposing characteristically started with outof-label use in single or series of cases, to continue after the first promising results with randomised clinical trials. There are several drugs that are currently tested in ongoing clinical trials: antimalarials hydroxychloroquine and chloroquine, HIV protease inhibitors lopinavir/ritonavir, broad spectrum antivirals umifenovir (anti-influenza drug) and favipiravir, antiparasitary drug ivermectin and nucleotide analogue remdesivir. However, up to date only a few trials are completed and published, precluding definitive conclusions about efficacy and safety of these drugs. Until major clinical trials are completed, physicians who decide to use these drugs out-of-label should properly inform their patients of all potential risks and benefits and seek for their consent before administration of the drugs.

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

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.

scholarly journals Drug Repurposing of Allophenylnorstatine Containing HIV-Protease Inhibitors Against SARS-CoV-2 Mpro: Insights from Molecular Dynamics Simulations and Binding Free Energy Estimations

2020 ◽  
Author(s):  
Jiban Jyoti Dash ◽  
Priyanka Purohit ◽  
Jules Tshishimbi Muya ◽  
Biswa Ranjan Meher
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Protease Inhibitors ◽  
Active Site ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Binding Affinities ◽  
Solvation Energies

Coronavirus-2 Main protease (SARS-CoV-2 M<sup>pro</sup>), one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and a crucial target for drug discovery, has been battered with numerous types of drugs/inhibitors. Regrettably, till date there is no any potential drugs or effective inhibitors available to combat its action. Based on the reports of HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M<sup>pro</sup>, we have chosen few clinically trialed experimental HIV-protease inhibitors (JE-2147, KNI-227 and KNI-272) and a variant JE2-CH3, to examine their binding affinities with SARS-CoV-2 M<sup>pro</sup> and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the rational elucidation of the binding mechanism of these four inhibitors to SARS-CoV-2 M<sup>pro</sup> by merging molecular docking, Molecular Dynamics (MD) simulation, and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (-14.95 kcal/mol) compared to JE2-CH3 (--11.19 kcal/mol), KNI-227 (-13.93 kcal/mol) and KNI-272 (-12.84 kcal/mol) against SARS-CoV-2 M<sup>pro</sup>. The increase in binding affinity for JE-2147 comparative to other three inhibitors arises due to an increased favorable van der Waals interactions and decreased solvation energies between the inhibitor and viral protease. Residue decomposition analysis and hydrogen bonding pattern confirms binding affinities of the inhibitors crucial for the interactions. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Pro168, Gln189 etc.) from the active site or near the active site regions with more than 1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 M<sup>pro</sup> drugs. <br>

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

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.

scholarly journals Evolution of drug resistance in HIV protease

2020 ◽  
Vol 21 (S18) ◽  
Author(s):  
Dhara Shah ◽  
Christopher Freas ◽  
Irene T. Weber ◽  
Robert W. Harrison
Keyword(s):  
Drug Resistance ◽  
Spanning Trees ◽  
Experimental Studies ◽  
Hiv Protease ◽  
Computational Techniques ◽  
Hiv Protease Inhibitors ◽  
Phenotype Data ◽  
The Face ◽  
Evolution Of Resistance ◽  
Selection For

Abstract Background Drug resistance is a critical problem limiting effective antiviral therapy for HIV/AIDS. Computational techniques for predicting drug resistance profiles from genomic data can accelerate the appropriate choice of therapy. These techniques can also be used to identify protease mutants for experimental studies of resistance and thereby assist in the development of next-generation therapies. Few studies, however, have assessed the evolution of resistance from genotype–phenotype data. Results The machine learning produced highly accurate and robust classification of resistance to HIV protease inhibitors. Genotype data were mapped to the enzyme structure and encoded using Delaunay triangulation. Estimates of evolutionary relationships, based on this encoding, and using Minimum Spanning Trees, showed clusters of mutations that closely resemble the wild type. These clusters appear to evolve uniquely to more resistant phenotypes. Conclusions Using the triangulation metric and spanning trees results in paths that are consistent with evolutionary theory. The majority of the paths show bifurcation, namely they switch once from non-resistant to resistant or from resistant to non-resistant. Paths that lose resistance almost uniformly have far lower levels of resistance than those which either gain resistance or are stable. This strongly suggests that selection for stability in the face of a rapid rate of mutation is as important as selection for resistance in retroviral systems.

scholarly journals Identification of Potential Inhibitors of SARS-CoV-2 Main Protease via a Rapid In-Silico Drug Repurposing Approach

2020 ◽  
Author(s):  
Cesar Mendoza-Martinez ◽  
Alejandro Rodriguez-Lezama
Keyword(s):  
In Silico ◽  
Antiviral Agents ◽  
Drug Repurposing ◽  
Binding Mode ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Binding Modes ◽  
Data Set ◽  
Main Protease ◽  
Potential Inhibitors

An in-silico drug repurposing study was carried out to search for potential COVID-19 antiviral agents. A dataset of 1615 FDA-approved drugs was docked in the active site of SARS CoV-2 Main protease. A subset of the top scoring hit compounds was subjected to follow-up molecular dynamics simulations to further characterise the predicted binding modes. The main findings are that the drugs Aliskiren, Capreomycin, Isovuconazonium, emerge as novel potential inhibitors. We also observed that Ceftolozane, Cobicistat, Carfilzomib and Saquinavir are well-ranked by our protocol, in agreement with other recent in silico drug repurposing studies, however MD simulations shows only potential for the three first, as Saquinavir exhibited an unstable binding mode. As many HIV-protease inhibitors has been reported as active and not active, Atazanavir and Lopinavir were included in the data set in order to rationalize the findings. In addition, our protocol ranked favourably Dronedarone suggesting that this recently reported SARS-CoV-2 inhibitor targets SARS-CoV-2 Main protease.

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