scholarly journals Structural Basis of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

2021 ◽  
Vol 9 ◽  
Author(s):  
Hylemariam Mihiretie Mengist ◽  
Tebelay Dilnessa ◽  
Tengchuan Jin
Keyword(s):  
Life Cycle ◽  
Patient Management ◽  
Social Economic ◽  
Structural Basis ◽  
Supportive Treatment ◽  
Future Directions ◽  
Main Protease ◽  
The World ◽  
Repurposed Drugs ◽  
Potential Inhibitors

The Coronavirus disease-19 (COVID-19) pandemic is still devastating the world causing significant social, economic, and political chaos. Corresponding to the absence of globally approved antiviral drugs for treatment and vaccines for controlling the pandemic, the number of cases and/or mortalities are still rising. Current patient management relies on supportive treatment and the use of repurposed drugs as an indispensable option. Of a crucial role in the viral life cycle, ongoing studies are looking for potential inhibitors to the main protease (Mpro) of severe acute respiratory syndrome Coronavirus -2 (SARS-CoV-2) to tackle the pandemic. Although promising results have been achieved in searching for drugs inhibiting the Mpro, work remains to be done on designing structure-based improved drugs. This review discusses the structural basis of potential inhibitors targeting SARS-CoV-2 Mpro, identifies gaps, and provides future directions. Further, compounds with potential Mpro based antiviral activity are highlighted.

scholarly journals Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease by Deep Docking of 1.3 Billion Compounds

2020 ◽  
Author(s):  
Anh-Tien Ton ◽  
Francesco Gentile ◽  
Michael Hsing ◽  
Fuqiang Ban ◽  
Artem Cherkasov
Keyword(s):  
Rapid Identification ◽  
Molecular Structures ◽  
Drug Candidates ◽  
Learning Platform ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Small Molecule Therapeutics ◽  
Novel Drug

<div>The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no FDA-approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vaccine or a small molecule therapeutics for SARS-CoV-2. Along these efforts, the structure of SARS-CoV-2 main protease (Mpro) has been rapidly resolved and made publicly available to facilitate global efforts to develop novel drug candidates.</div><div>In recent month, our group has developed a novel deep learning platform – Deep Docking (DD) which enables very fast docking of billions of molecular structures and provides up to 6,000X enrichment on the top-predicted ligands compared to conventional docking workflow (without notable loss of information on potential hits). In the current work we applied DD to entire 1.3 billion compounds from ZINC15 library to identify top 1,000 potential ligands for SARS-CoV-2 Mpro. The compounds are made publicly available for further characterization and development by scientific community.</div>

Discovery of Potent SARS-CoV-2 Inhibitors from Approved Antiviral Drugs via Docking Screening

2020 ◽  
Vol 23 ◽  
Author(s):  
Samir Chtita ◽  
Assia Belhassan ◽  
Adnane Aouidate ◽  
Salah Belaidi ◽  
Mohammed Bouachrine ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Hiv Protease ◽  
Potential Effectiveness ◽  
Main Protease ◽  
The World ◽  
Potential Inhibitors ◽  
Anti Hiv

Background: Corona Virus Disease 2019 (COVID-19) pandemic threatens patients, societies and healthcare systems around the world. There is an emergent need to search for possible medications. Objective: This article intends to use virtual screening and molecular docking methods to find potential inhibitors that can respond to COVID-19 from existing drugs. Methods: To tack part in the current research investigation to define a potential target drug that may protect the world from emerged pandemic corona disease, we have carried out a virtual screening study by of 129 approved drugs that their metabolic characteristics, dosages used, potential efficacy and side effects are clear as they have been approved for treating existing infections. Especially 12 drugs against chronic hepatitis B virus, 37 against chronic hepatitis C virus, 37 against human immunodeficiency virus, 14 anti-herpesvirus, 11 anti- influenza, and 18 others drugs currently on the market were considered for this study. Then these drugs were evaluated using virtual screening and molecular docking studies in the active site of the (SARS-CoV-2) main protease (6lu7). Once the efficacy of the drug is determined, it can be approved for of their in vitro and in vivo activity against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that could be interesting for rapid clinical treatment of patients. These drugs were ranked for potential effectiveness against SARS-CoV-2 and those with high molecular docking scores are proposed as novel candidates for repurposing. The N3 inhibitor co-crystallized with the protease (6lu7) and the anti-HIV protease inhibitor Lopinavir were used as standards for comparison. : These drugs were ranked for potential effectiveness against SARS-CoV-2 and those with high molecular docking scores are proposed as novel candidates for repurposing. The N3 inhibitor co-crystallized with the protease (6lu7) and the anti-HIV protease inhibitor Lopinavir were used as standards for comparison. Results: The results suggest the effectiveness of Beclabuvir, Nilotinib, Tirilazad, Trametinib and Glecaprevir as potent drugs against SARS-CoV-2 since they tightly bind to its main protease. Conclusion: These promising drugs could inhibit the replication of the virus; hence, we suggest the repurposing of these compounds for thetreatment of COVID-19. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. However, the assessment of these potential inhibitors as clinical drugs involves further in vivo tests for these drugs.

scholarly journals A Survey of Inhibitors for the Main Protease of Coronaviruses with the Potential for Development of Broad-Spectrum Therapeutics

2021 ◽  
Vol 17 (4) ◽  
pp. 71-84
Author(s):  
Alyssa Sanders ◽  
Samuel Ricci ◽  
Sarah Uribe ◽  
Bridget Boyle ◽  
Brian Nepper ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Broad Spectrum ◽  
Active Site ◽  
Human Life ◽  
Neuraminidase Inhibitor ◽  
Main Protease ◽  
The World ◽  
Potential Inhibitors

The coronaviruses plaguing humanity in the 21st century share much in common: a spontaneous route of origin from wild animals, a propensity to take human life, and, importantly, a highly conserved set of biological machinery necessary for viral replication. Most recently, the SARS-CoV-2 is decimating economies around the world and has claimed over two million human lives, reminding the world of a need for an effective drug against present and future coronaviruses. To date, attempts to repurpose clinically approved antiviral medications show minimal promise, highlighting the need for development of new antiviral drugs. Nucleotide analog inhibitors are a promising therapeutic candidate, but early data from clinical studies suggests these compounds have limited efficacy. However, novel compounds targeting the main protease responsible for critical steps in viral assembly are gaining considerable interest because they offer the potential for broad-spectrum coronavirus therapy. Here, we review the literature regarding potential inhibitors for the main protease of coronaviruses, especially SARS-CoV-2, analyze receptor-drug interactions, and draw conclusions about candidate inhibitors for future outbreaks. Promising candidates for development of a broad-spectrum coronavirus protease inhibitor include the neuraminidase inhibitor 3K, the peptidomimetic inhibitor 11a and 11b, the α-ketoamide inhibitor 13b, the aldehyde prodrug, and the phosphate prodrug developed by Pfizer. In silico and in vitro analyses have shown that these inhibitors strongly interact with the active site of the main protease, and to varying degrees, prevent viral replication via interactions with the largely conserved active site pockets. KEYWORDS: Severe Acute Respiratory Syndrome Coronavirus; Middle East Respiratory Syndrome Coronavirus; Severe Acute Respiratory Syndrome Coronavirus 2; Replicase Polypeptide; Protease; Neuraminidase Inhibitor; Peptidomimetic Inhibitor; α-Ketoamide Inhibitor; Molecular Docking

Catechin Derivatives as Inhibitor of COVID-19 Main Protease (Mpro): Molecular Docking studies unveils an opportunity against CORONA

2020 ◽  
Vol 23 ◽  
Author(s):  
Muhammad Nouman Arif
Keyword(s):  
Docking Studies ◽  
Ligand Docking ◽  
World Population ◽  
Docking Analysis ◽  
Main Protease ◽  
Antiretroviral Drug ◽  
Medicinal Use ◽  
The World ◽  
Potential Inhibitors ◽  
Synthetic Derivatives

Background: A new stain of corona virus COVID-19 got worldwide attention and has affected almost whole of the world population. Currently there is no specific vaccine or drug against COVID-19. Xu et al. (2020) built a homolog model of SARS-CoV-2 Mpro based on SARS-CoV Mpro which is considered as target to inhibit the replication of CoV. Objective: The aim of current study is to find potential inhibitors of COVID-19 Mpro using docking analysis. Methods: Autodockvina was used to carry out Protein-Ligand docking. COVID-19 main protease Mpro was docked with catechin and its different synthetic derivatives. Nelfinavir is an antiretroviral drug belongs to protease inhibitors was taken as standard. Results: According to the result obtained it was found that Compound (4) and Compound (1) have more affinity than nelfinavir. Conclusion: Compounds have a great potential to become COVID-19 main protease Mpro inhibitor. Nevertheless for their medicinal use further investigation is necessary.

scholarly journals Drug Repurposing and Polypharmacology to Fight SARS-CoV-2 Through Inhibition of the Main Protease

2021 ◽  
Vol 12 ◽  
Author(s):  
Luca Pinzi ◽  
Annachiara Tinivella ◽  
Fabiana Caporuscio ◽  
Giulio Rastelli
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Inhibitory Activity ◽  
Therapeutic Indication ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Main Protease ◽  
The World ◽  
Potential Inhibitors ◽  
Late Stages

The outbreak of a new coronavirus (SARS-CoV-2), which is responsible for the COVID-19 disease and is spreading rapidly around the world, urgently requires effective therapeutic treatments. In this context, drug repurposing represents a valuable strategy, as it enables accelerating the identification of drug candidates with already known safety profiles, possibly aiding in the late stages of clinical evaluation. Moreover, therapeutic treatments based on drugs with beneficial multi-target activities (polypharmacology) may show an increased antiviral activity or help to counteract severe complications concurrently affecting COVID-19 patients. In this study, we present the results of a computational drug repurposing campaign that aimed at identifying potential inhibitors of the main protease (Mpro) of the SARS-CoV-2. The performedin silicoscreening allowed the identification of 22 candidates with putative SARS-CoV-2 Mproinhibitory activity. Interestingly, some of the identified compounds have recently entered clinical trials for COVID-19 treatment, albeit not being assayed for their SARS-CoV-2 antiviral activity. Some candidates present a polypharmacology profile that may be beneficial for COVID-19 treatment and, to the best of our knowledge, have never been considered in clinical trials. For each repurposed compound, its therapeutic relevance and potential beneficial polypharmacological effects that may arise due to its original therapeutic indication are thoroughly discussed.

scholarly journals Structure Based Screening Of Fungal Bioactive Metabolites As Potential Inhibitors Of Main Protease (Mpro) Of SARS-CoV-2

2021 ◽  
Author(s):  
Ashish Saraf ◽  
Meghna Shrivastava ◽  
K K Shukla
Keyword(s):  
Viral Particle ◽  
Antimicrobial Agents ◽  
Preventive Measure ◽  
Bioactive Metabolites ◽  
Dodecanoic Acid ◽  
Fungal Metabolites ◽  
Main Protease ◽  
The World ◽  
Potential Inhibitors ◽  
In Silico Molecular Docking

Abstract The pandemic disease COVID-19 has put the world into a massive threat. Till now no effective treatment has been established and the world is applying lockdowns as a preventive measure against this. Recent studies have identified that COVID-19 main protease (Mpro) is essential for its life cycle and is responsible for the proteolytic mutation of this virus. Thus, destruction of the complete viral particle can be achieved through inhibition of this main protease. The fungal metabolites have already been proved as potential antimicrobial agents hence were selected for in-silico molecular docking, to check their affinity towards COVID-19 main protease. Metabolites like 2H-oxecin-3-one,3,4,7,8,9,10hexahydro-4-methoxy-10-methyl, Eicosanoic acid phenylmethyl ester, HEPES, 2,4-dihydroxy,2,5-dimethyl-furan(3)one and Dodecanoic acid-3-hydroxy have revealed strong binding affinity towards the main protease. Thus, the present study enlightens a path to combat COVID-19 by the use of bioactive metabolites.

scholarly journals Drug repurposing and polypharmacology to fight SARS-CoV-2 through the inhibition of the main protease

2020 ◽  
Author(s):  
Luca Pinzi ◽  
Annachiara Tinivella ◽  
Fabiana Caporuscio ◽  
Giulio Rastelli
Keyword(s):  
Crystal Structure ◽  
Therapeutic Indication ◽  
Severe Disease ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Drugbank Database

Abstract There is an urgent need to develop therapeutic options to fight the outbreak of a novel Coronavirus (SARS-CoV-2), which causes a disease named COVID-19 and is spreading rapidly around the world. Drug repurposing can significantly accelerate the identification of drug candidates suitable for clinical evaluation. Moreover, drugs with polypharmacological effects may increase antiviral activity and/or counteract severe disease complications concurrently affecting COVID-19 patients. Herein, we present the results of a computational drug repurposing campaign in search for potential inhibitors of the main protease of SARS-CoV-2. To this aim, the complete DrugBank database, including drug metabolites, was docked to the recently solved crystal structure of the SARS-CoV-2 Mpro and the results were post-processed by using our in-house tool BEAR. Here we report 32 promising drugs that could be repositioned to fight SARS-CoV-2. Some of them have already entered clinical trials against COVID-19, thus supporting our results, but the vast majority of the selected compounds is new and has never been considered before. For each repurposed compound its therapeutic relevance and the potential beneficial polypharmacological effects that may arise thanks to its original therapeutic indication are thoroughly discussed.

scholarly journals Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease by Deep Docking of 1.3 Billion Compounds

2020 ◽  
Author(s):  
Anh-Tien Ton ◽  
Francesco Gentile ◽  
Michael Hsing ◽  
Fuqiang Ban ◽  
Artem Cherkasov
Keyword(s):  
Rapid Identification ◽  
Molecular Structures ◽  
Drug Candidates ◽  
Learning Platform ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Small Molecule Therapeutics ◽  
Novel Drug

<div>The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no FDA-approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vaccine or a small molecule therapeutics for SARS-CoV-2. Along these efforts, the structure of SARS-CoV-2 main protease (Mpro) has been rapidly resolved and made publicly available to facilitate global efforts to develop novel drug candidates.</div><div>In recent month, our group has developed a novel deep learning platform – Deep Docking (DD) which enables very fast docking of billions of molecular structures and provides up to 6,000X enrichment on the top-predicted ligands compared to conventional docking workflow (without notable loss of information on potential hits). In the current work we applied DD to entire 1.3 billion compounds from ZINC15 library to identify top 1,000 potential ligands for SARS-CoV-2 Mpro. The compounds are made publicly available for further characterization and development by scientific community.</div>

scholarly journals Drug repurposing and polypharmacology to fight SARS-CoV-2 through the inhibition of the main protease

2020 ◽  
Author(s):  
Luca Pinzi ◽  
Annachiara Tinivella ◽  
Fabiana Caporuscio ◽  
Giulio Rastelli
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Therapeutic Indication ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Main Protease ◽  
The World ◽  
Novel Coronavirus ◽  
Potential Inhibitors ◽  
Selection Of

Abstract Therapeutic options are urgently needed to fight the outbreak of a novel coronavirus (SARS-CoV-2), which causes the COVID-19 disease and is spreading rapidly around the world. Drug repurposing can significantly accelerate the identification of drug candidates suitable for clinical evaluation. Moreover, polypharmacological effects may increase antiviral activity and/or counteract severe complications concurrently affecting COVID-19 patients. Herein, we present the results of a computational drug repurposing campaign in search of potential inhibitors of the main protease of SARS-CoV-2. The screening allowed the selection of 22 promising drugs. Some of them have already entered clinical trials, but the vast majority of the identified compounds are new and have never been considered before. For each repurposed compound, its therapeutic relevance and potential beneficial polypharmacological effects that may arise due to its original therapeutic indication are thoroughly discussed.

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