In silico mining of terpenes from red-sea invertebrates for SARS-CoV-2 main protease (Mpro) inhibitors

Mahmoud A.A. Ibrahim, Alaa H.M. Abdelrahman, Tarik A. Mohamed, Mohamed A.M. Atia, Montaser A.M. Al-Hammady, Khlood A.A. Abdeljawaad, Eman M. Elkady, Mahmoud F. Moustafa, Faris Alrumaihi, Khaled S. Allemailem, Hesham R. El-Seedi, Paul W. Paré, Thomas Efferth, Mohamed Elamir F. Hegazy

Research output: Contribution to journalArticlepeer-review

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ∆Gbinding ≤ −40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ∆Gbinding values of −51.9 vs. −33.6 kcal/mol, respectively. Protein–protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine-and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target–function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.

Original languageEnglish
Article number2082
JournalMolecules
Volume26
Issue number7
DOIs
StatePublished - Apr 1 2021

Keywords

  • Drug discovery
  • Marine natural products
  • Molecular docking
  • Molecular dynamics
  • SARS-CoV-2 main protease
  • Virtual drug screening

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