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

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

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 (M(pro)) 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 M(pro) inhibitors with ΔG(binding) ≤ −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 M(pro) than lopinavir over 100 ns with ΔG(binding) 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.