Journal Article

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

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

2021

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Antiretroviral drugs / Antiviral drugs / Binding Sites / Coronaviruses / COVID-19 - virology / COVID-19 Drug Treatment / COVID-19 vaccines / Disease transmission / drug discovery / Enzymes / Genomes / Humans / Hydrogen Bonding / Hydrogen bonds / Invertebrates / Invertebrates - chemistry / Invertebrates - metabolism / Ligands / Lopinavir - chemistry / Lopinavir - metabolism / marine natural products / Metabolites / molecular docking / Molecular Docking Simulation / molecular dynamics / Molecular Dynamics Simulation / Mutation / Natural products / Protease Inhibitors - chemistry / Protease Inhibitors - isolation & purification / Protease Inhibitors - therapeutic use / Protein Binding / Proteins / SARS-CoV-2 - isolation & purification / SARS-CoV-2 - metabolism / SARS-CoV-2 main protease / Severe acute respiratory syndrome coronavirus 2 / Simulation / Terpenes - chemistry / Terpenes - isolation & purification / Terpenes - metabolism / Terpenes - therapeutic use / Thermodynamics / Viral Matrix Proteins - antagonists & inhibitors / Viral Matrix Proteins - metabolism / virtual drug screening