Plant‐derived chemicals as potential inhibitors of SARS‐CoV ‐2 main protease ( 6LU7 ), a virtual screening study

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (Mpro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 Mpro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 Mpro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 Mpro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

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Consensus Virtual Screening of Dark Chemical Matter and Food Chemicals Uncover Potential Inhibitors of SARS-CoV-2 Main Protease

10.26434/chemrxiv.12420860 ◽

2020 ◽

Author(s):

Marisa G. Santibáñez-Morán ◽

Edgar López-López ◽

Fernando D. Prieto-Martínez ◽

Norberto Sánchez-Cruz ◽

Jose L. Medina-Franco

Keyword(s):

Virtual Screening ◽

Chemical Space ◽

Experimental Testing ◽

Consensus Approach ◽

Computational Tools ◽

Drug Candidates ◽

Main Protease ◽

Selection For ◽

Potential Inhibitors ◽

Chemical Matter

The COVID-19 pandemic caused by SARS-CoV-2 has claimed more than 380,000 lives Worldwide and more than 6.5 million people are infected. Unfortunately, there is no drug or vaccine for the treatment of COVID-19. The increasing information available of key molecular targets of SARS-CoV-2 and active compounds against related coronavirus facilitates computational tools to rapidly suggest drug candidates for the treatment of COVID-19. As part of a global effort to fight the COVID-19 pandemic, herein we report a consensus virtual screening of large collections of food chemicals and compounds classified as Dark Chemical Matter. The rationale is to complement global efforts and explore regions of the chemical space currently underexplored. The consensus approach included combining similarity searching with various queries and fingerprints, molecular docking with two docking programs, and ADMETox profiling. We propose three compounds commercially available that were sent to experimental testing. We disclose the full list of virtual screening hits that can be subject to additional selection for acquisition or synthesis and experimental testing. This manuscript will be updated when the experimental testing of the selected compounds becomes available.

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Repurposing of FDA Approved Drugs for the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease

10.26434/chemrxiv.12278066 ◽

2020 ◽

Author(s):

Abhik Kumar Ray ◽

Parth Sarthi Sen Gupta ◽

Saroj Kumar Panda ◽

Satyaranjan Biswal ◽

Malay Kumar Rana

Keyword(s):

Virtual Screening ◽

Binding Energies ◽

Great Promise ◽

Main Protease ◽

Promising Target ◽

Inhibitory Potential ◽

Novel Coronavirus ◽

Approved Drugs ◽

Potential Inhibitors ◽

Fda Approved Drugs

<p>COVID-19, responsible for several deaths, demands a cumulative effort of scientists worldwide to curb the pandemic. The main protease, responsible for the cleavage of the polyprotein and formation of replication complex in virus, is considered as a promising target for the development of potential inhibitors to treat the novel coronavirus. The effectiveness of FDA approved drugs targeting the main protease in previous SARS-COV (s) reported earlier indicates the chances of success for the repurposing of FDA drugs against SARS-COV-2. Therefore, in this study, molecular docking and virtual screening of FDA approved drugs, primarily of three categories: antiviral, antimalarial, and peptide, are carried out to investigate their inhibitory potential against the main protease. Virtual screening has identified 53 FDA drugs on the basis of their binding energies (< -7.0 kcal/mol), out of which the top two drugs Velpatasvir (-9.1 kcal/mol) and Glecaprevir (-9.0 kcal/mol) seem to have great promise. These drugs have a stronger affinity to the SARS-CoV-2 main protease than the crystal bound inhibitor α-ketoamide 13B (-6.7 kcal/mol) or Indinavir (-7.5 kcal/mol) that has been proposed in a recent study as one of the best drugs for SARS-CoV-2. The <i>in-silico</i> efficacies of the screened drugs could be instructive for further biochemical and structural investigation for repurposing. The molecular dynamics studies on the shortlisted drugs are underway. </p>

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ABBV-744 as a potential inhibitor of SARS-CoV-2 main protease enzyme against COVID-19

Scientific Reports ◽

10.1038/s41598-020-79918-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zeynab Fakhar ◽

Shama Khan ◽

Suliman Y. AlOmar ◽

Afrah Alkhuriji ◽

Aijaz Ahmad

Keyword(s):

Virtual Screening ◽

Drug Repurposing ◽

Pharmacophore Modeling ◽

Binding Energies ◽

Active Inhibitor ◽

Lead Compounds ◽

Protease Enzyme ◽

Main Protease ◽

Dynamics Simulations ◽

Potential Inhibitors

AbstractA new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening workflow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the selected lead compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered lead compounds. Binding energies revealed that compound ABBV-744 binds to the Mpro with strong affinity (ΔGbind −45.43 kcal/mol), and the complex is more stable in comparison with other protein–ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

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ABBV-744 and Onalespid as Potential Inhibitors of SARS-CoV-2 main Protease Enzyme: A Promising Therapeutics in COVID-19?

10.21203/rs.3.rs-37619/v1 ◽

2020 ◽

Author(s):

Zeynab Fakhar ◽

Shama Khan ◽

Aijaz Ahmad

Keyword(s):

Virtual Screening ◽

Drug Repurposing ◽

Pharmacophore Modeling ◽

Binding Studies ◽

Active Inhibitor ◽

Lead Compounds ◽

Protease Enzyme ◽

Main Protease ◽

Dynamics Simulations ◽

Potential Inhibitors

Abstract A new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening work-flow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the best hit compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered compounds. Binding studies revealed that compound ABBV-744 binds to the Mpro with strong affinity (Gbind -45.43 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

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

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323999200730205447 ◽

2020 ◽

Vol 23 ◽

Cited By ~ 3

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.

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