A student led computational screening of peptide inhibitors against main protease of SARS‐CoV ‐2

Objective: At present, the coronavirus disease (COVID)-19 pandemic is increasing global health concerns. This coronavirus outbreak is caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2. Since, no specific antiviral for treatment against COVID-19, so identification of new therapeutics is an urgent need. The objective of this study is to the analysis of lichen compounds against main protease and spike protein targets of SARS-CoV-2 using in silico approach. Methods: A total of 108 lichen compounds were subjected to ADMET analysis and 14 compounds were selected based on the ADMET properties and Lipinski’s rule of five. Molecular docking was performed for screening of selected individual lichen metabolites against the main protease and spike proteins of SARS-CoV-2 by Schrodinger Glide module software. Results: Among the lead compounds, fallacinol showed the highest binding energy value of −11.83 kcal/mol against spike protein, 4-O-Demethylbarbatic acid exhibited the highest dock score of −11.67 kcal/mol against main protease. Conclusion: This study finding suggests that lichen substances may be potential inhibitors of SARS-CoV-2.

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Computational screening for potential drug candidates against the SARS-CoV-2 main protease

F1000Research ◽

10.12688/f1000research.23829.1 ◽

2020 ◽

Vol 9 ◽

pp. 514 ◽

Cited By ~ 2

Author(s):

Bruno Silva Andrade ◽

Preetam Ghosh ◽

Debmalya Barh ◽

Sandeep Tiwari ◽

Raner José Santana Silva ◽

...

Keyword(s):

Natural Compounds ◽

Potential Drug ◽

Drug Candidates ◽

Positive Effects ◽

Computational Screening ◽

Main Protease ◽

Zinc Database ◽

Structural Assembly

Background: SARS-CoV-2 is the causal agent of the current coronavirus disease 2019 (COVID-19) pandemic. They are enveloped, positive-sense, single-stranded RNA viruses of the Coronaviridae family. Proteases of SARS-CoV-2 are necessary for viral replication, structural assembly, and pathogenicity. The approximately 33.8 kDa Mpro protease of SARS-CoV-2 is a non-human homologue and is highly conserved among several coronaviruses, indicating that Mpro could be a potential drug target for Coronaviruses. Methods: Herein, we performed computational ligand screening of four pharmacophores (OEW, remdesivir, hydroxychloroquine and N3) that are presumed to have positive effects against SARS-CoV-2 Mpro protease (6LU7), and also screened 50,000 natural compounds from the ZINC Database dataset against this protease target. Results: We found 40 pharmacophore-like structures of natural compounds from diverse chemical classes that exhibited better affinity of docking as compared to the known ligands. The 11 best selected ligands, namely ZINC1845382, ZINC1875405, ZINC2092396, ZINC2104424, ZINC44018332, ZINC2101723, ZINC2094526, ZINC2094304, ZINC2104482, ZINC3984030, and ZINC1531664, are mainly classified as beta-carboline, alkaloids, and polyflavonoids, and all displayed interactions with dyad CYS145 and HIS41 from the protease pocket in a similar way as other known ligands. Conclusions: Our results suggest that these 11 molecules could be effective against SARS-CoV-2 protease and may be subsequently tested in vitro and in vivo to develop novel drugs against this virus.

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Computational Screening for Potential Drug Candidates Against SARS-CoV-2 Main Protease

10.20944/preprints202004.0003.v2 ◽

2020 ◽

Cited By ~ 1

Author(s):

Bruno Andrade ◽

Preetam Ghosh ◽

Debmalya Barth ◽

Sandeep Tiwari ◽

Raner José Santana Silva ◽

...

Keyword(s):

Potential Drug ◽

Drug Candidates ◽

Positive Effects ◽

Computational Screening ◽

Main Protease ◽

Zinc Database ◽

Novel Drugs ◽

Structural Assembly

Background: SARS-CoV-2 that are the causal agent of a current pandemic are enveloped, positive-sense, single-stranded RNA viruses of the Coronaviridae family. Proteases of SARS-CoV-2 are necessary for viral replication, structural assembly and pathogenicity. The ~33.8KDa Mpro protease of SARS-CoV-2 is a non-human homologue and highly conserved among several coronaviruses indicating Mpro could be a potential drug target for Coronaviruses.Methods: Here we performed computational ligand screening of four pharmacophores (OEW, Remdesivir, Hydroxycholoquine and N3) that are presumed to have positive effects against SARS-CoV-2 Mpro protease (6LU7) and also screened 50,000 molecules from the ZINC Database dataset against this protease target.Results: We found 40 pharmacophore-like structures of natural compounds from diverse chemical classes that exhibited better affinity of docking as compared to the known ligands. The 10 best selected ligands namely, ZINC1845382, ZINC1875405, ZINC2092396, ZINC2104424, ZINC44018332, ZINC2101723, ZINC2094526, ZINC2094304, ZINC2104482, ZINC3984030, and ZINC1531664, are mainly classified as β-carboline, Alkaloids and Polyflavonoids, and all of them displayed interactions with dyad CYS145 and HIS41 from the protease pocket in a similar way as with other known ligands.Conclusion: Our results suggest that these 10 molecules could be effective against SARS-CoV-2 protease and may be tested in vitro and in vivo to develop novel drugs against this virus.

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Computational Screening for Potential Drug Candidates Against SARS-CoV-2 Main Protease

10.20944/preprints202004.0003.v1 ◽

2020 ◽

Author(s):

Bruno Andrade ◽

Preetam Ghosh ◽

Debmalya Barth ◽

Sandeep Tiwari ◽

Raner José Santana Silva ◽

...

Keyword(s):

Potential Drug ◽

Drug Candidates ◽

Positive Effects ◽

Computational Screening ◽

Main Protease ◽

Zinc Database ◽

Novel Drugs ◽

Structural Assembly

Background: SARS-CoV-2 that are the causal agent of a current pandemic are enveloped, positive-sense, single-stranded RNA viruses of the Coronaviridae family. Proteases of SARS-CoV-2 are necessary for viral replication, structural assembly and pathogenicity. The ~33.8KDa Mpro protease of SARS-CoV-2 is a non-human homologue and highly conserved among several coronaviruses indicating Mpro could be a potential drug target for Coronaviruses.Methods: Here we performed computational ligand screening of four pharmacophores (OEW, Remdesivir, Hydroxycholoquine and N3) that are presumed to have positive effects against SARS-CoV-2 Mpro protease (6LU7) and also screened 50,000 molecules from the ZINC Database dataset against this protease target.Results: We found 40 pharmacophore-like structures of natural compounds from diverse chemical classes that exhibited better affinity of docking as compared to the known ligands. The 10 best selected ligands namely, ZINC1845382, ZINC1875405, ZINC2092396, ZINC2104424, ZINC44018332, ZINC2101723, ZINC2094526, ZINC2094304, ZINC2104482, ZINC3984030, and ZINC1531664, are mainly classified as β-carboline, Alkaloids and Polyflavonoids, and all of them displayed interactions with dyad CYS145 and HIS41 from the protease pocket in a similar way as with other known ligands.Conclusion: Our results suggest that these 10 molecules could be effective against SARS-CoV-2 protease and may be tested in vitro and in vivo to develop novel drugs against this virus.

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Structure-based identification of SARS-CoV-2 main protease inhibitors from anti-viral specific chemical libraries: an exhaustive computational screening approach

Molecular Diversity ◽

10.1007/s11030-021-10214-6 ◽

2021 ◽

Author(s):

Shovonlal Bhowmick ◽

Achintya Saha ◽

Sameh Mohamed Osman ◽

Fatmah Ali Alasmary ◽

Tahani Mazyad Almutairi ◽

...

Keyword(s):

Free Energy ◽

Large Scale ◽

Chemical Space ◽

Binding Free Energy ◽

Dynamic State ◽

Replication Process ◽

Specific Chemical ◽

Chemical Libraries ◽

Computational Screening ◽

Main Protease

Abstract Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease (Mpro). Particularly, viewing the large-scale biological role of Mpro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-dock and MM-GBSA cut-off scores as −8.00 and −45.00 kcal/mol, chemical space has been further reduced. Exhaustive molecular binding interactions analyses and various pharmacokinetics profiles assessment suggested four compounds (ChemDiv_D658-0159, ChemDiv_F431-0433, Enamine_Z3019991843 and Asinex_LAS_51389260) as potent inhibitors/modulators of SARS-CoV-2 Mpro. In-depth protein–ligand interactions stability in the dynamic state has been evaluated by 100 ns molecular dynamics (MD) simulation studies along with MM-GBSA-based binding free energy estimations of entire simulation trajectories that have revealed strong binding affinity of all identified compounds towards Mpro. Hence, all four identified compounds might be considered as promising candidates for future drug development specifically targeting the SARS-CoV-2 Mpro; however, they also need experimental assessment for a better understanding of molecular interaction mechanisms. Graphic abstract

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Discovery of SARS-CoV-2 Mpro Peptide Inhibitors from Modelling Substrate and Ligand Binding

10.1101/2021.06.18.446355 ◽

2021 ◽

Author(s):

H. T. Henry Chan ◽

Marc A. Moesser ◽

Rebecca K. Walters ◽

Tika R. Malla ◽

Rebecca M. Twidale ◽

...

Keyword(s):

Critical Role ◽

Md Simulations ◽

Peptide Inhibitors ◽

Binding Modes ◽

Molecular Features ◽

Main Protease ◽

Modelling Studies ◽

Viral Lifecycle ◽

Computational Mutagenesis

The main protease (Mpro) of SARS-CoV-2 is central to its viral lifecycle and is a promising drug target, but little is known concerning structural aspects of how it binds to its 11 natural cleavage sites. We used biophysical and crystallographic data and an array of classical molecular mechanics and quantum mechanical techniques, including automated docking, molecular dynamics (MD) simulations, linear-scaling DFT, QM/MM, and interactive MD in virtual reality, to investigate the molecular features underlying recognition of the natural Mpro substrates. Analyses of the subsite interactions of modelled 11-residue cleavage site peptides, ligands from high-throughput crystallography, and designed covalently binding inhibitors were performed. Modelling studies reveal remarkable conservation of hydrogen bonding patterns of the natural Mpro substrates, particularly on the N-terminal side of the scissile bond. They highlight the critical role of interactions beyond the immediate active site in recognition and catalysis, in particular at the P2/S2 sites. The binding modes of the natural substrates, together with extensive interaction analyses of inhibitor and fragment binding to Mpro, reveal new opportunities for inhibition. Building on our initial Mpro-substrate models, computational mutagenesis scanning was employed to design peptides with improved affinity and which inhibit Mpro competitively. The combined results provide new insight useful for the development of Mpro inhibitors.

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Discovery of Antiviral Cyclic Peptides Targeting the Main Protease of SARS-CoV-2 via mRNA Display

10.1101/2021.08.23.457419 ◽

2021 ◽

Author(s):

Jason Johansen-Leete ◽

Sven Ullrich ◽

Sarah Fry ◽

Rebecca Frkic ◽

Max Bedding ◽

...

Keyword(s):

Cyclic Peptides ◽

Cyclic Peptide ◽

Peptide Inhibitors ◽

Mrna Display ◽

High Affinity ◽

Main Protease ◽

Binding Epitope ◽

Affinity Peptide ◽

Micromolar Range

Antivirals that specifically target SARS-CoV-2 are needed to control the COVID-19 pandemic. The main protease (Mpro) is essential for SARS-CoV-2 replication and is an attractive target for antiviral development. Here we report the use of the Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display on a chemically cross-linked SARS-CoV-2 Mpro dimer, which yielded several high-affinity thioether-linked cyclic peptide inhibitors of the protease. Structural analysis of Mpro complexed with a selenoether analogue of the highest-affinity peptide revealed key binding interactions, including glutamine and leucine residues in sites S1 and S2, respectively, and a binding epitope straddling both protein chains in the physiological dimer. Several of these Mpro peptide inhibitors possessed antiviral activity against SARS-CoV-2 in vitro with EC50 values in the low micromolar range. These cyclic peptides serve as a foundation for the development of much needed antivirals that specifically target SARS-CoV-2.

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