In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors

Mahmoud A A Ibrahim; Alaa H M Abdelrahman; Taha A Hussien; Esraa A A Badr; Tarik A Mohamed; Hesham R El-Seedi; Paul W Pare; Thomas Efferth; Mohamed-Elamir F Hegazy

doi:10.1016/j.compbiomed.2020.104046

In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors

Comput Biol Med. 2020 Nov:126:104046. doi: 10.1016/j.compbiomed.2020.104046. Epub 2020 Oct 8.

Authors

Mahmoud A A Ibrahim¹, Alaa H M Abdelrahman², Taha A Hussien³, Esraa A A Badr², Tarik A Mohamed⁴, Hesham R El-Seedi⁵, Paul W Pare⁶, Thomas Efferth⁷, Mohamed-Elamir F Hegazy⁸

Affiliations

¹ Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt. Electronic address: m.ibrahim@compchem.net.
² Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, 61519, Egypt.
³ Pharmacognosy Department, Faculty of Pharmacy, Deraya University, Minia, Egypt.
⁴ Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza, 12622, Egypt.
⁵ Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, S-106 91, Stockholm, Sweden; International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, 212013, China.
⁶ Department of Chemistry & Biochemistry Texas Tech University, Lubbock, TX, 79409 USA.
⁷ Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.
⁸ Chemistry of Medicinal Plants Department, National Research Centre, 33 El-Bohouth St., Dokki, Giza, 12622, Egypt; Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany. Electronic address: me.fathy@nrc.sci.eg.

Abstract

Coronavirus Disease 2019 (COVID-19) is an infectious illness caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), originally identified in Wuhan, China (December 2019) and has since expanded into a pandemic. Here, we investigate metabolites present in several common spices as possible inhibitors of COVID-19. Specifically, 32 compounds isolated from 14 cooking seasonings were examined as inhibitors for SARS-CoV-2 main protease (M^pro), which is required for viral multiplication. Using a drug discovery approach to identify possible antiviral leads, in silico molecular docking studies were performed. Docking calculations revealed a high potency of salvianolic acid A and curcumin as M^pro inhibitors with binding energies of -9.7 and -9.2 kcal/mol, respectively. Binding mode analysis demonstrated the ability of salvianolic acid A and curcumin to form nine and six hydrogen bonds, respectively with amino acids proximal to M^pro's active site. Stabilities and binding affinities of the two identified natural spices were calculated over 40 ns molecular dynamics simulations and compared to an antiviral protease inhibitor (lopinavir). Molecular mechanics-generalized Born surface area energy calculations revealed greater salvianolic acid A affinity for the enzyme over curcumin and lopinavir with energies of -44.8, -34.2 and -34.8 kcal/mol, respectively. Using a STRING database, protein-protein interactions were identified for salvianolic acid A included the biochemical signaling genes ACE, MAPK14 and ESR1; and for curcumin, EGFR and TNF. This study establishes salvianolic acid A as an in silico natural product inhibitor against the SARS-CoV-2 main protease and provides a promising inhibitor lead for in vitro enzyme testing.

Keywords: Molecular docking; Molecular dynamics; SARS-CoV-2 main protease; Secondary metabolites; Spices.

MeSH terms

Betacoronavirus / enzymology*
COVID-19
Caffeic Acids / chemistry*
Caffeic Acids / therapeutic use
Coronavirus 3C Proteases
Coronavirus Infections / drug therapy*
Coronavirus Infections / enzymology
Curcumin / chemistry*
Curcumin / therapeutic use
Cysteine Endopeptidases* / chemistry
Drug Discovery*
Humans
Lactates / chemistry*
Lactates / therapeutic use
Molecular Docking Simulation*
Molecular Dynamics Simulation*
Pandemics
Pneumonia, Viral / drug therapy*
Pneumonia, Viral / enzymology
Protease Inhibitors / chemistry*
Protease Inhibitors / therapeutic use
SARS-CoV-2
Thermodynamics
Viral Nonstructural Proteins* / antagonists & inhibitors
Viral Nonstructural Proteins* / chemistry

Substances

Caffeic Acids
Lactates
Protease Inhibitors
Viral Nonstructural Proteins
salvianolic acid A
Cysteine Endopeptidases
Coronavirus 3C Proteases
Curcumin