Abstract
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.
Highlights
Coronavirus (CoV) belonging to the Coronaviridae family is one of the largest families of positive-sense, RNA viruses [1]
Based on the Reactome mining, we found that 340 showed a potential therapeutic effect (Hit:32/144 with false discovery rate (FDR):9.17E-1) against SARS-CoV-2 viral infection (Figure S4)
COVID-19 is a universal risk for positive human health and economic losses continue to build unabated
Summary
Coronavirus (CoV) belonging to the Coronaviridae family is one of the largest families of positive-sense, RNA viruses [1]. CoVs are recognized to cause infection in the respiratory, hepatic, enteric and neurological systems and pandemic conditions have ensued with high infection rates [3]. Since the World Health Organization (WHO) announced this new beta coronavirus in late. 2019, cataloged as SARS-CoV-2 (COVID-19) [4], the organization has authorized several. COVID-19 preparations for emergency use immunization including vaccines developed by Pfizer/BioNTech, Astrazeneca/Oxford, Serum Institute of India, Johnson & Johnson, Moderna and Sinopharm. Notwithstanding these advances in controlling the pandemic, with high viral transmission via respiratory droplets from coughing and/or sneezing [5], there is still an urgency to developing effective antiviral drugs for COVID-19 treatment
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