Discovery of Potent Covid-19 Main Protease Inhibitors Using Machine Learning Based Virtual Screening Strategy

The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel antiviral therapies are urgently needed to overcome this pandemic. Given the great role of main protease of Covid-19 for virus replication, we performed drug repurposing study using recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR respectively were developed using available small molecule inhibitors and utilized in the screening of DrugBank repository. Further, hierarchical docking protocol was implemented with the support of Glide algorithm. The resultant compounds were then examined for its binding free energy against main protease of Covid-19 by means of Prime-MM/GBSA algorithm. Most importantly, the resultant compounds antiviral activities were further predicted by machine learning-based model generated by AutoQSAR algorithm. Finally, the hit molecules were examined for its drug likeness and its toxicity parameters through QikProp algorithm. Overall, the present analysis yielded four potential inhibitors (DB07800, DB08573, DB03744 and DB02986) that are predicted to bind with main protease of Covid-19 better than currently used drug molecules such as N3 (co-crystallized native ligand), Lopinavir and Ritonavir.

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

10.26434/chemrxiv.12199610 ◽

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.

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

10.26434/chemrxiv.12199610.v1 ◽

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.

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Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

10.26434/chemrxiv.12228831 ◽

2020 ◽

Author(s):

Shruti Koulgi ◽

Vinod Jani ◽

Mallikarjunachari Uppuladinne ◽

Uddhavesh Sonavane ◽

Asheet Kumar Nath ◽

...

Keyword(s):

Drug Repurposing ◽

Drug Binding ◽

Ensemble Docking ◽

Drug Molecules ◽

Drug Binding Site ◽

Main Protease ◽

Docking Approach ◽

Novel Coronavirus ◽

Markov State Modeling ◽

Viral Polyprotein

The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CLpro (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This in-silico ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.

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

Molecular Informatics ◽

10.1002/minf.202000187 ◽

2021 ◽

Author(s):

Nemanja Djokovic ◽

Dusan Ruzic ◽

Teodora Djikic ◽

Sandra Cvijic ◽

Jelisaveta Ignjatovic ◽

...

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Main Protease ◽

Potential Inhibitors

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Computational Determination of Potential Inhibitors of SARS-CoV-2 Main Protease

10.26434/chemrxiv.12111297 ◽

2020 ◽

Author(s):

Son Tung Ngo ◽

Ngoc Quynh Anh Pham ◽

Ly Le ◽

Duc-Hung Pham ◽

Van Vu

Keyword(s):

Free Energy ◽

Molecular Docking ◽

Drug Targets ◽

Binding Free Energy ◽

Natural Compounds ◽

Main Protease ◽

Energy Perturbation ◽

Novel Coronavirus ◽

Potential Inhibitors ◽

Hiv 1

The novel coronavirus (SARS-CoV-2) has infected over 850,000 people and caused more than 42000 deaths worldwide as of April 1st, 2020. As the disease is spreading rapidly all over the world, it is urgent to find effective drugs to treat the virus. The main protease (Mpro) of SARS-CoV-2 is one of the potential drug targets. In this work, we used rigorous computational methods, including molecular docking, fast pulling of ligand (FPL), and free energy perturbation (FEP), to investigate potential inhibitors of SARS-CoV-2 Mpro. We first tested our approach with three reported inhibitors of SARS-CoV-2 Mpro; and our computational results are in good agreement with the respective experimental data. Subsequently, we applied our approach on a databases of ~4600 natural compounds found in Vietnamese plants, as well as 8 available HIV-1 protease (PR) inhibitors and an aza-peptide epoxide. Molecular docking resulted in a short list of 35 natural compounds, which was subsequently refined using the FPL scheme. FPL simulations resulted in five potential inhibitors, including 3 natural compounds and two available HIV-1 PR inhibitors. Finally, FEP, the most accurate and precise method, was used to determine the absolute binding free energy of these five compounds. FEP results indicate that two natural compounds, cannabisin A and isoacteoside, and an HIV-1 PR inhibitor, darunavir, exhibit large binding free energy to SARS-CoV-2 Mpro, which is larger than that of 13b, the most reliable SARS-CoV-2 Mpro inhibitor recently reported. The binding free energy largely arises from van der Waals (vdW) interaction. We also found that Glu166 form H-bonds to all the inhibitors. Replacing Glu166 by an alanine residue leads to ~ 2.0 kcal/mol decreases in the affinity of darunavir to SARS-CoV-2 Mpro. Our results could contribute to the development of potentials drugs inhibiting SARS-CoV-2.

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Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

10.26434/chemrxiv.12204668 ◽

2020 ◽

Author(s):

Ancy Iruthayaraj ◽

Sivanandam Magudeeswaran ◽

Kumaradhas Poomani

Keyword(s):

Clinical Trial ◽

Amino Acids ◽

Free Energy ◽

Binding Free Energy ◽

Drug Repurposing ◽

Md Simulations ◽

Binding Mechanism ◽

Main Protease ◽

Repurposed Drugs ◽

Hiv 1

Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (Mpro) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (Mpro). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 Mpro. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of Mpro enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of Mpro and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This in silico study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 Mpro enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.

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

10.26434/chemrxiv.12629858 ◽

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

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.

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

10.26434/chemrxiv.12449081.v1 ◽

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

The recent 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 (Mpro, 3CLpro). 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.

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In silico Screening of Natural Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike RBD: Targets for COVID-19

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.599079 ◽

2021 ◽

Vol 7 ◽

Author(s):

Divya M. Teli ◽

Mamta B. Shah ◽

Mahesh T. Chhabria

Keyword(s):

Binding Free Energy ◽

Treatment Options ◽

Natural Compounds ◽

Pharmacokinetic Parameters ◽

Main Protease ◽

Glide Docking ◽

Docking Approach ◽

Covalent Docking ◽

Dual Inhibitors ◽

Potential Inhibitors

Historically, plants have been sought after as bio-factories for the production of diverse chemical compounds that offer a multitude of possibilities to cure diseases. To combat the current pandemic coronavirus disease 2019 (COVID-19), plant-based natural compounds are explored for their potential to inhibit the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of COVID-19. The present study is aimed at the investigation of antiviral action of several groups of phytoconstituents against SARS-CoV-2 using a molecular docking approach to inhibit Main Protease (Mpro) (PDB code: 6LU7) and spike (S) glycoprotein receptor binding domain (RBD) to ACE2 (PDB code: 6M0J) of SARS-CoV-2. For binding affinity evaluation, the docking scores were calculated using the Extra Precision (XP) protocol of the Glide docking module of Maestro. CovDock was also used to investigate covalent docking. The OPLS3e force field was used in simulations. The docking score was calculated by preferring the conformation of the ligand that has the lowest binding free energy (best pose). The results are indicative of better potential of solanine, acetoside, and rutin, as Mpro and spike glycoprotein RBD dual inhibitors. Acetoside and curcumin were found to inhibit Mpro covalently. Curcumin also possessed all the physicochemical and pharmacokinetic parameters in the range. Thus, phytochemicals like solanine, acetoside, rutin, and curcumin hold potential to be developed as treatment options against COVID-19.

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