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


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.


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


Ibrahim, M.A.A., Abdelrahman, A.H.M., Mohamed, T.A., Atia, M.A.M., Al-Hammady, M.A.M., Abdeljawaad, K.A.A., Elkady, E.M., Moustafa, M.F., Alrumaihi, F., Allemailem, K.S., El-Seedi, H.R., Pare, P.W., Efferth, T., & Hegazy, M.-E.F.. 2021. In silico mining of terpenes from red-sea invertebrates for SARS-CoV-2 main protease (Mpro) inhibitors. Molecules, 26(7).