In Silico Mining of Terpenes from Red-Sea Invertebrates for SARS-CoV-2 Main Protease (Mpro) Inhibitors.

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 ΔGbinding ≤ -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 ΔGbinding 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.

• Authors: 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
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 26 Issue 7 (Apr 05 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 33916461 (Publication Type: Journal Article)

Chemical References

• Protease Inhibitors
• Terpenes
• Viral Matrix Proteins
• membrane protein, SARS-CoV-2
• Lopinavir

Topics

• Animals
• Binding Sites
• COVID-19 (virology)
• Humans
• Hydrogen Bonding
• Invertebrates (chemistry, metabolism)
• Lopinavir (chemistry, metabolism)
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Protease Inhibitors (chemistry, isolation & purification, therapeutic use)
• Protein Binding
• SARS-CoV-2 (isolation & purification, metabolism)
• Terpenes (chemistry, isolation & purification, metabolism, therapeutic use)
• Thermodynamics
• Viral Matrix Proteins (antagonists & inhibitors, metabolism)
• COVID-19 Drug Treatment