Blue biotechnology: Computational screening of sarcophyton cembranoid diterpenes for sars-cov-2 main protease inhibition

Mahmoud A.A. Ibrahim, Alaa H.M. Abdelrahman, Mohamed A.M. Atia, Tarik A. Mohamed, Mahmoud F. Moustafa, Abdulrahim R. Hakami, Shaden A.M. Khalifa, Fahad A. Alhumaydhi, Faris Alrumaihi, Syed Hani Abidi, Khaled S. Allemailem, Thomas Efferth, Mahmoud E. Soliman, Paul W. Paré, Hesham R. El-Seedi, Mohamed Elamir F. Hegazy

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ∆Gbinding < −33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ∆Gbinding values of −43.8 and −34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to remodulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.

Original languageEnglish
Article number391
JournalMarine Drugs
Volume19
Issue number7
DOIs
StatePublished - Jul 2021

Keywords

  • Cembranoid diterpenes metabolites
  • Genus Sarcophyton
  • Molecular docking
  • Molecular dynamics
  • Reactome
  • SARS-CoV-2 main protease

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