Blue Biotechnology: Computational Screening of Sarcophyton Cembranoid Diterpenes for SARS-CoV-2 Main Protease Inhibition

Mar Drugs. 2021 Jul 13;19(7):391. doi: 10.3390/md19070391.


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 ΔGbinding < -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 ΔGbinding 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 re-modulate 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.

Keywords: SARS-CoV-2 main protease; cembranoid diterpenes metabolites; genus Sarcophyton; molecular docking; molecular dynamics; reactome.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anthozoa / chemistry*
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / metabolism
  • Coronavirus Protease Inhibitors / chemistry
  • Coronavirus Protease Inhibitors / isolation & purification
  • Coronavirus Protease Inhibitors / pharmacology*
  • Diterpenes / chemistry
  • Diterpenes / isolation & purification
  • Diterpenes / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology
  • SARS-CoV-2 / pathogenicity
  • Structure-Activity Relationship


  • Coronavirus Protease Inhibitors
  • Diterpenes
  • Coronavirus 3C Proteases