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 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.

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 Prioritization of Potential Drugs Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Yanjin Li ◽  
Yu Zhang ◽  
Yikai Han ◽  
Tengfei Zhang ◽  
Ranran Du
Keyword(s):  
Large Scale ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Neural Activities ◽  
Main Protease ◽  
Global Threat ◽  
Potential Inhibitors ◽  
Molecular Patterns ◽  
Effective Drugs ◽  
Large Scale Screening

<p> Since its outbreak in 2019, the acute respiratory syndrome caused by SARS-Cov-2 has become a severe global threat to human. The lack of effective drugs strongly limits the therapeutic treatment against this pandemic disease. Here we employed a computational approach to prioritize potential inhibitors that directly target the core enzyme of SARS-Cov-2, the main protease, which is responsible for processing the viral RNA-translated polyprotein into functional proteins for viral replication. Based on a large-scale screening of over 13, 000 drug-like molecules, we have identified the most potential drugs that may suffice drug repurposing for SARS-Cov-2. Importantly, the second top hit is Beclabuvir, a known replication inhibitor of hepatitis C virus (HCV), which is recently reported to inhibit SARS-Cov-2 as well. We also noted several neurotransmitter-related ligands among the top candidates, suggesting a novel molecular similarity between this respiratory syndrome and neural activities. Our approach not only provides a comprehensive list of prioritized drug candidates for SARS-Cov-2, but also reveals intriguing molecular patterns that are worth future explorations.</p>

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>

Prioritization of Potential Drugs Targeting the SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Yanjin Li ◽  
Yu Zhang ◽  
Yikai Han ◽  
Tengfei Zhang ◽  
Ranran Du
Keyword(s):  
Large Scale ◽  
Drug Repurposing ◽  
Drug Candidates ◽  
Neural Activities ◽  
Main Protease ◽  
Global Threat ◽  
Potential Inhibitors ◽  
Molecular Patterns ◽  
Effective Drugs ◽  
Large Scale Screening

<p> Since its outbreak in 2019, the acute respiratory syndrome caused by SARS-Cov-2 has become a severe global threat to human. The lack of effective drugs strongly limits the therapeutic treatment against this pandemic disease. Here we employed a computational approach to prioritize potential inhibitors that directly target the core enzyme of SARS-Cov-2, the main protease, which is responsible for processing the viral RNA-translated polyprotein into functional proteins for viral replication. Based on a large-scale screening of over 13, 000 drug-like molecules, we have identified the most potential drugs that may suffice drug repurposing for SARS-Cov-2. Importantly, the second top hit is Beclabuvir, a known replication inhibitor of hepatitis C virus (HCV), which is recently reported to inhibit SARS-Cov-2 as well. We also noted several neurotransmitter-related ligands among the top candidates, suggesting a novel molecular similarity between this respiratory syndrome and neural activities. Our approach not only provides a comprehensive list of prioritized drug candidates for SARS-Cov-2, but also reveals intriguing molecular patterns that are worth future explorations.</p>

scholarly journals DRUG REPURPOSING FOR MALARIA AND DENGUE USING COMPUTATIONAL MODELLING.

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Prajakta Velankar ◽  
Sara Rehman ◽  
Yukti Thakkar
Keyword(s):  
Clinical Trials ◽  
Drug Design ◽  
Antiviral Activity ◽  
Computational Modelling ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
Quantum Mechanical ◽  
Rational Drug ◽  
The World ◽  
Approved Drugs

By and by the world is in a battle with the diseases like Malaria and Dengue with no prompt medicines accessible the scourge brought about by the Malaria and Dengue is expanding step by step. A ton of researchers are continuing for the potential medication up-and-comer that could help the medical care framework in this battle. We present a docking?based screening using a quantum mechanical scoring of a library built from approved drugs ie Remdesivir, Hydroxy-chloroquine, Curcumin, Moroxydine, Artesunate Sulphate, Mefloquine, Doxycycline, Atovaquone, Indinavir, and compounds that are with Malaria and Dengue Mpro Proteins could display antiviral activity against these diseases. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against Malaria and Dengue Keywords: Malaria, Dengue, Drug Repurposings, Computer Aid Drug Design, In silico drug development

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 An Integrative in Silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS‐CoV‐2 Main Protease

2021 ◽  
Author(s):  
Nemanja Djokovic ◽  
Dusan Ruzic ◽  
Teodora Djikic ◽  
Sandra Cvijic ◽  
Jelisaveta Ignjatovic ◽  
...  
Keyword(s):  
In Silico ◽  
Drug Repurposing ◽  
Main Protease ◽  
Potential Inhibitors

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 Main Protease Inhibitors and Drug Surface Hotspot for the Treatment of COVID-19: Drug Repurposing and Molecular Docking Approach

2020 ◽  
Author(s):  
Mahmudul Hasan ◽  
Md Sorwer Alam Parvez ◽  
Kazi Faizul Azim ◽  
Abdus Shukur Imran ◽  
Topu Raihan ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Repurposing ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Drug Candidates ◽  
Target Drug ◽  
Global Pandemic ◽  
Main Protease ◽  
Docking Approach ◽  
Repurposed Drugs

<div>The world is facing an unprecedented global pandemic caused by the novel SARS-CoV-2. In the absence</div><div>of a specific therapeutic agent to treat COVID-19 patients, the present study aimed to virtually screen out</div><div>the effective drug candidates from the approved main protease protein (MPP) inhibitors and their</div><div>derivatives for the treatment of SARS-CoV-2. Here, drug repurposing and molecular docking were</div><div>employed to screen approved MPP inhibitors and their derivatives. The approved MPP inhibitors against</div><div>HIV and HCV were prioritized, whilst hydroxychloroquine, favipiravir, remdesivir, and alpha-ketoamide</div><div>were studied as control. The target drug surface hotspot was also investigated through the molecular</div><div>docking technique. ADME analysis was conducted to understand the pharmacokinetics and drug-likeness</div><div>of the screened MPP inhibitors. The result of this study revealed that Paritaprevir (-10.9 kcal/mol), and its</div><div>analog (CID 131982844)(-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitor</div><div>compared in this study including favipiravir, remdesivir, and alpha-ketoamide. A comparative study among</div><div>the screened putative MPP inhibitors revealed that amino acids T25, T26, H41, M49, L141, N142, G143,</div><div>C145, H164, M165, E166, D187, R188, and Q189 are at critical positions for becoming the surface hotspot</div><div>in the MPP of SARS-CoV-2. The study also suggested that paritaprevir and its' analog (CID 131982844),</div><div>may be effective against SARS-CoV-2 as these molecules had the common drug-surface hotspots on the</div><div>main protease protein of SARS-CoV-2. Other pharmacokinetic parameters also indicate that paritaprevir</div><div>and its top analog (CID 131982844) will be either similar or better-repurposed drugs than already approved</div><div>MPP inhibitors. </div><div><br></div>

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