scholarly journals Potential inhibitors of protease 3CLpro virus COVID-19: drug reposition

2020 ◽  
Vol 3 (1) ◽  
pp. e00124
Author(s):  
V.S. Skvortsov ◽  
D.S. Druzhilovskiy ◽  
A.V. Veselovsky
Keyword(s):  
Drug Development ◽  
Kinase Inhibitor ◽  
Experimental Testing ◽  
Docking Simulation ◽  
Hiv Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Drug Reposition ◽  
Approved Drugs ◽  
Potential Inhibitors

Pneumonia caused by the COVID-19 virus has led to quick search of drugs that would able to block the spread of this virus. A standard way of drug development is a long process. One approach that can significantly accelerate drug development is drug reposition. In this study a virtual screening of the database of approved drugs has been used for search inhibitors against 3СLpro COVID-19, the main protease of COVID-19. Molecular docking, simulation of molecular dynamics and binding energy estimation by MM-GBSA method allowed to select several compounds for further experimental testing. The most promising drugs are the HIV protease inhibitor Indinavir, the inhibitor of protease hepatitis C Telaprevir, the antiulcer drug Dalargin, and the ErB receptor tyrosine kinase inhibitor Neratinib

scholarly journals Virtual Screening of Potential Inhibitors for SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Carlos Javier Alméciga-Díaz ◽  
Luisa N. Pimentel-Vera ◽  
Angela Caro ◽  
Angela Mosquera ◽  
Camilo Andrés Castellanos Moreno ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Clinical Information ◽  
Virus Genome ◽  
Pharmacological Agents ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Potential Inhibitors

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.

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

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.

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

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>

scholarly journals Drug Repurposing and New Therapeutic Strategies for SARS-CoV-2 Disease Using a Novel Molecular Modeling-AI Hybrid Workflow

2020 ◽  
Author(s):  
Scott Bembenek
Keyword(s):  
Molecular Modeling ◽  
Therapeutic Targets ◽  
Drug Repurposing ◽  
Preclinical Research ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Usual Process ◽  
Potential Inhibitors ◽  
Computational Platform

<p>The recent<b> </b>outbreak of the novel coronavirus (SARS-CoV-2) poses a significant challenge to the scientific and medical communities to find immediate treatments. The usual process of identifying viable molecules and transforming them into a safe and effective drug takes 10-15 years, with around 5 years of that time spent in preclinical research and development alone. The fastest strategy is to identify existing drugs or late-stage clinical molecules (originally intended for other therapeutic targets) that already have some level of efficacy. To this end, we tasked our novel molecular modeling-AI hybrid computational platform with finding potential inhibitors of the SARS-CoV-2 main protease (M<sup>pro</sup>, 3CL<sup>pro</sup>). Over 13,000 FDA-approved drugs and clinical candidates (represented by just under 30,000 protomers) were examined. This effort resulted in the identification of several promising molecules. Moreover, it provided insight into key chemical motifs surely to be beneficial in the design of future inhibitors. Finally, it facilitated a unique perspective into other potentially therapeutic targets and pathways for SARS-CoV-2.</p>

scholarly journals Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Dileep Francis ◽  
Sadasivan C
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Target ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Energy Calculation ◽  
Viral Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

Drug Repurposing and New Therapeutic Strategies for SARS-CoV-2 Disease Using a Novel Molecular Modeling-AI Hybrid Workflow

2020 ◽  
Author(s):  
Scott Bembenek
Keyword(s):  
Molecular Modeling ◽  
Therapeutic Targets ◽  
Drug Repurposing ◽  
Preclinical Research ◽  
Main Protease ◽  
Novel Coronavirus ◽  
Approved Drugs ◽  
Usual Process ◽  
Potential Inhibitors ◽  
Computational Platform

<p>The recent<b> </b>outbreak of the novel coronavirus (SARS-CoV-2) poses a significant challenge to the scientific and medical communities to find immediate treatments. The usual process of identifying viable molecules and transforming them into a safe and effective drug takes 10-15 years, with around 5 years of that time spent in preclinical research and development alone. The fastest strategy is to identify existing drugs or late-stage clinical molecules (originally intended for other therapeutic targets) that already have some level of efficacy. To this end, we tasked our novel molecular modeling-AI hybrid computational platform with finding potential inhibitors of the SARS-CoV-2 main protease (M<sup>pro</sup>, 3CL<sup>pro</sup>). Over 13,000 FDA-approved drugs and clinical candidates (represented by just under 30,000 protomers) were examined. This effort resulted in the identification of several promising molecules. Moreover, it provided insight into key chemical motifs surely to be beneficial in the design of future inhibitors. Finally, it facilitated a unique perspective into other potentially therapeutic targets and pathways for SARS-CoV-2.</p>

scholarly journals Repurposing Simeprevir, Calpain Inhibitor IV and a Cathepsin F Inhibitor Against SARS-CoV-2: A Study Using in Silico Pharmacophore Modeling and Docking Methods

2020 ◽  
Author(s):  
Abhithaj J ◽  
Dileep Francis ◽  
Sharanya C.S ◽  
arun kumar ◽  
Sadasivan C ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Rapid Development ◽  
Pharmacophore Modeling ◽  
Host Cells ◽  
Calpain Inhibitor ◽  
Energy Estimation ◽  
Fitness Score ◽  
Main Protease ◽  
Cathepsin F ◽  
Approved Drugs

The world has come to a sudden halt due to the incessant spread of a viral pneumonia dubbed COVID-19 caused by the beta-coronavirus, SARS-CoV-2. The pandemic spread of the virus has already claimed lakhs of valuable lives and has infected millions of people across the globe. The situation is further worsened by the fact that there is no approved therapeutics currently available for the treatment of the disease. The only way to handle the crisis is the rapid development of a therapeutic strategy to combat the virus. Computational biology offers resources to rapidly identify novel drug leads and to repurpose existing drugs at the expense of minimal resources and time. The main protease of SARS-CoV-2 is key to the replication and propogation of the virus in the host cells. Inhibiting the protease blocks replication and hence is an attractive therapeutic target in the virus. The crystal structures of the protein in complex with inhibitors are available in public databases. Here we describe the screening of the DrugBank database, a public repository for small molecule therapeutics, to identify approved or experimental phase drugs that can be repurposed against the main protease of SARS-CoV2. The initial screening was performed on more than 13,000 drug entries in the target database using an energy optimised pharmacophore hypothesis AARRR. A sub-set of the molecules selected based on the fitness score was further screened using molecular docking by sequentially filtering the molecules through the high throughput virtual screening, extra precision and standard precision docking modalities. The most promising hits were subjected to binding free energy estimation using the MMGBSA method. Approved drugs viz, Cobicistat, Larotrectinib and Simeprevir were identified as potential candidates for repurposing. Drugs in the discovery phase identified as inhibitors include the known cysteine protease inhibitors, Calpain inhibitor IV and an experimental cathepsin F inhibitor.

scholarly journals Molecular Docking and Fragment-Based QSAR Modeling for In Silico Screening of Approved Drugs and Candidate Compounds Against COVID-19

2020 ◽  
Vol 8 (2) ◽  
pp. 83-88
Author(s):  
Saeid Afshar ◽  
Asrin Bahmani ◽  
Massoud Saidijam
Keyword(s):  
Molecular Docking ◽  
Autodock Vina ◽  
Qsar Modeling ◽  
Health Crisis ◽  
Mortality And Morbidity ◽  
Main Protease ◽  
Docking Calculations ◽  
Approved Drugs ◽  
Top 40 ◽  
Potential Inhibitors

Background: Coronavirus disease 2019 (COVID-19) as a serious global health crisis leads to high mortality and morbidity. However, currently, there are no effective vaccines and treatments for COVID-19. Main protease (Mpro) and angiotensin-converting enzyme 2 (ACE2) are the best therapeutic targets of COVID-19. Objectives: The main purpose of this study is to investigate the most appropriate drug and candidate compound for proper interaction with Mpro and ACE2 to inhibit the activity of COVID-19. Methods: In this study, repurposing of approved drugs and screening of candidate compounds using molecular docking and fragment-based QSAR method were performed to discover the potential inhibitors of Mpro and ACE2. QSAR and docking calculations were performed based on the prediction of the inhibitory activities of 5-hydroxy indanone derivatives. Based on the results, an optimal structure was proposed to inhibit the activity of COVID-19. Results: Among 2629 DrugBank approved drugs, 118 were selected considering the LibDock score and absolute energy for possible drug-Mpro interactions. Furthermore, the top 40 drugs were selected based on screening the results for possible drug- Mpro interactions with AutoDock Vina. Conclusion: Finally, evaluation of the top 40 selected drugs for possible drug-ACE2 interactions with AutoDock Vina indicated that deslanoside (DB01078) can interact effectively with both Mpro and ACE2. However, prior to conducting clinical trials, further experimental validation is needed.

scholarly journals Drug Repurposing Against SARS-CoV-2 Using E-Pharmacophore Based Virtual Screening and Molecular Docking with Main Protease as the Target

2020 ◽  
Author(s):  
arun kumar ◽  
Sharanya C.S ◽  
Abhithaj J ◽  
Dileep Francis ◽  
Sadasivan C
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Drug Target ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Energy Calculation ◽  
Viral Protease ◽  
Energy Estimation ◽  
Main Protease ◽  
Potential Inhibitors

Since its first report in December 2019 from China the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 26 lakh, and claiming the lives of more than 1.8 lakh individuals across the globe. Although social quarantine measures have succeeded in containing the spread of the virus to some extent, the lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using the crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor as the drug target. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits were further screened using a structure based approach involving molecular docking at different precisions. The most promising drugs were subjected to binding free energy estimation using MM-GBSA. Among the 4600 drugs screened 17 drugs were identified as candidate inhibitors of the viral protease based on the glide scores obtained from molecular docking. Binding free energy calculation showed that six drugs viz, Binifibrate, Macimorelin acetate, Bamifylline, Rilmazafon, Afatinib and Ezetimibe can act as potential inhibitors of the viral protease.

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.

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