In-silico Discovery of Fungal Metabolites Bergenin, Quercitrin and Dihydroartemisinin as Potential Inhibitors against Main Protease of SARS-CoV-2

Emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has given rise to COVID-19 pandemic, that is wreaking havoc worldwide. Therefore, there is an urgent need to find out novel drugs to combat SARS-CoV-2 infection. In this backdrop, the present study was aimed to assess potent bioactive compounds from different fungi as potential inhibitors of SARS-CoV-2 main protease (Mpro) using an in-silico analysis. Nearly 118 bioactive compounds were extracted from Dictyophora indusiata, Geassstrum triplex and Cyathus stercoreus and identified using HR LC/MS analysis. Of which, only bergenin (D. indusiata), quercitrin (G. triplex) and dihydroartemisinin (C. stercoreus) were selected based on their medicinal uses, binding score and active site covered. The 6LU7, a protein crystallographic structure of SARS-CoV-2 Mpro, was docked with bergenin, quercitrin and dihydroartemisinin using Autodock 4.2 and the binding energies obtained were -7.86, -10.29 and -7.20 kcal/mol, respectively. Bergenin, quercitrin and dihydroartemisinin formed hydrogen bond, electrostatic interactions and hydrophobic interactions with foremost active site amino acids THR190, GLU166, GLN189, GLY143, HIS163, HIS164, CYS145 and PHE140. Present investigation suggests that these three drugs may be used as alternative inhibitors against SARS-CoV-2 Mpro. However, further research is necessary to assess in vitro potential of these drugs. To the best of our knowledge, present investigation reported these three bioactive compounds of fungal origin for the first time.

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Discovery of Fungal Metabolites Bergenin, Quercitrin and Dihydroartemisinin as Potential Inhibitors Against Main Protease of SARS-CoV-2

10.26434/chemrxiv.12523136.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ravi Patel ◽

Akash Vanzara ◽

Nimisha Patel ◽

Ajit Vasava ◽

Sachin Patil ◽

...

Keyword(s):

Bioactive Compounds ◽

Active Site ◽

Electrostatic Interactions ◽

Hydrophobic Interactions ◽

Binding Energies ◽

Crystallographic Structure ◽

Medicinal Uses ◽

Main Protease ◽

Cyathus Stercoreus ◽

Potential Inhibitors

Emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has given rise to COVID-19 pandemic, that is wreaking havoc worldwide. Therefore, there is an urgent need to find out novel drugs to combat SARS-CoV-2 infection. In this backdrop, the present study was aimed to assess potent bioactive compounds from different fungi as potential inhibitors of SARS-CoV-2 main protease (Mpro) using an in-silico analysis. Nearly 118 bioactive compounds were extracted from Dictyophora indusiata, Geassstrum triplex and Cyathus stercoreus and identified using HR LC/MS analysis. Of which, only bergenin (D. indusiata), quercitrin (G. triplex) and dihydroartemisinin (C. stercoreus) were selected based on their medicinal uses, binding score and active site covered. The 6LU7, a protein crystallographic structure of SARS-CoV-2 Mpro, was docked with bergenin, quercitrin and dihydroartemisinin using Autodock 4.2 and the binding energies obtained were -7.86, -10.29 and -7.20 kcal/mol, respectively. Bergenin, quercitrin and dihydroartemisinin formed hydrogen bond, electrostatic interactions and hydrophobic interactions with foremost active site amino acids THR190, GLU166, GLN189, GLY143, HIS163, HIS164, CYS145 and PHE140. Present investigation suggests that these three drugs may be used as alternative inhibitors against SARS-CoV-2 Mpro. However, further research is necessary to assess in vitro potential of these drugs. To the best of our knowledge, present investigation reported these three bioactive compounds of fungal origin for the first time.

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In silico studies of selected xanthophylls as potential candidates against SARS-CoV-2 targeting main protease (Mpro) and papain-like protease (PLpro)

Herba Polonica ◽

10.2478/hepo-2021-0009 ◽

2021 ◽

Vol 67 (2) ◽

pp. 1-8

Author(s):

Tomasz M. Karpiński ◽

Marek Kwaśniewski ◽

Marcin Ożarowski ◽

Rahat Alam

Keyword(s):

Binding Energy ◽

Active Site ◽

In Silico ◽

Active Sites ◽

Data Bank ◽

Pharmacokinetic Parameters ◽

Discovery Studio ◽

Main Protease ◽

In Silico Studies ◽

Potential Inhibitors

Summary Introduction: The main protease (Mpro) and the papain-like protease (PLpro) are essential for the replication of SARS-CoV-2. Both proteases can be targets for drugs acting against SARS-CoV-2. Objective: This paper aims to investigate the in silico activity of nine xanthophylls as inhibitors of Mpro and PLpro. Methods: The structures of Mpro (PDB-ID: 6LU7) and PLpro (PDB-ID: 6W9C) were obtained from RCSB Protein Data Bank and developed with BIOVIA Discovery Studio. Active sites of proteins were performed using CASTp. For docking the PyRx was used. Pharmacokinetic parameters of ADMET were evaluated using SwissADME and pkCSM. Results: β-cryptoxanthin exhibited the highest binding energy: –7.4 kcal/mol in the active site of Mpro. In PLpro active site, the highest binding energy had canthaxanthin of –9.4 kcal/mol, astaxanthin –9.3 kcal/mol, flavoxanthin –9.2 kcal/mol and violaxanthin –9.2 kcal/mol. ADMET studies presented lower toxicity of xanthophylls in comparison to ritonavir and ivermectin. Conclusion: Our findings suggest that xanthophylls can be used as potential inhibitors against SARS-CoV-2 main protease and papain-like protease.

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In silico investigation of potential inhibitors to main protease and spike protein of SARS-CoV-2 in propolis

Biochemistry and Biophysics Reports ◽

10.1016/j.bbrep.2021.100969 ◽

2021 ◽

pp. 100969

Author(s):

Azza H. Harisna ◽

Rizky Nurdiansyah ◽

Putri H. Syaifie ◽

Dwi W. Nugroho ◽

Kurniawan E. Saputro ◽

...

Keyword(s):

In Silico ◽

Spike Protein ◽

Main Protease ◽

Potential Inhibitors

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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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In Silico Identification of Potential Inhibitors of the Main Protease of SERS-CoV-2 Using Combined Ligand-based and Structure-based Drug Design approach

Eurasian Journal of Medicine and Oncology ◽

10.14744/ejmo.2020.91768 ◽

2020 ◽

Author(s):

Sudhan Debnath

Keyword(s):

Drug Design ◽

In Silico ◽

Design Approach ◽

Structure Based Drug Design ◽

Main Protease ◽

In Silico Identification ◽

Potential Inhibitors

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In silico validation of coumarin derivatives as potential inhibitors against Main Protease, NSP10/NSP16-Methyltransferase, Phosphatase and Endoribonuclease of SARS CoV-2

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1808075 ◽

2020 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Akhilesh Kumar Maurya ◽

Nidhi Mishra

Keyword(s):

In Silico ◽

Coumarin Derivatives ◽

Main Protease ◽

Potential Inhibitors

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The dolabellane diterpenes as potential inhibitors of the SARS-CoV-2 main protease: molecular insight of the inhibitory mechanism through computational studies

RSC Advances ◽

10.1039/d1ra07584e ◽

2021 ◽

Vol 11 (62) ◽

pp. 39455-39466

Author(s):

Nanik Siti Aminah ◽

Muhammad Ikhlas Abdjan ◽

Andika Pramudya Wardana ◽

Alfinda Novi Kristanti ◽

Imam Siswanto ◽

...

Keyword(s):

In Silico ◽

Computational Studies ◽

Inhibitory Mechanism ◽

Main Protease ◽

Potential Inhibitors

An investigation on dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CLpro) using an in silico approach.

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Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site

Nature Communications ◽

10.1038/s41467-020-19662-4 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Jaeyong Lee ◽

Liam J. Worrall ◽

Marija Vuckovic ◽

Federico I. Rosell ◽

Francesco Gentile ◽

...

Keyword(s):

Conformational Changes ◽

Active Site ◽

Catalytic Mechanism ◽

Bound State ◽

Crystallographic Structure ◽

Wild Type ◽

Site Mutation ◽

Main Protease ◽

Dimerization Interface ◽

Enzyme Intermediate

AbstractSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes the disease COVID-19, produces replicase polyproteins 1a and 1ab that contain, respectively, 11 or 16 nonstructural proteins (nsp). Nsp5 is the main protease (Mpro) responsible for cleavage at eleven positions along these polyproteins, including at its own N- and C-terminal boundaries, representing essential processing events for subsequent viral assembly and maturation. We have determined X-ray crystallographic structures of this cysteine protease in its wild-type free active site state at 1.8 Å resolution, in its acyl-enzyme intermediate state with the native C-terminal autocleavage sequence at 1.95 Å resolution and in its product bound state at 2.0 Å resolution by employing an active site mutation (C145A). We characterize the stereochemical features of the acyl-enzyme intermediate including critical hydrogen bonding distances underlying catalysis in the Cys/His dyad and oxyanion hole. We also identify a highly ordered water molecule in a position compatible for a role as the deacylating nucleophile in the catalytic mechanism and characterize the binding groove conformational changes and dimerization interface that occur upon formation of the acyl-enzyme. Collectively, these crystallographic snapshots provide valuable mechanistic and structural insights for future antiviral therapeutic development including revised molecular docking strategies based on Mpro inhibition.

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