The SARS-CoV-2 main protease (Mpro) is an internally encoded protease which serves to hydrolyze the translated polyproteins at designated sites. It directly mediates viral replication hence a promising and main target for drug design. Plant-based natural products provide scaffold for many effective antiviral medications, and are recently shown to be able to inhibit the SARS-CoV-2 Mpro. Polyphenols and phenolic compounds are a major class of bioactive natural compounds that are known for their antiviral and pleiotropic effects, which are also reported to be effective in Mpro activity inhibitions. This work focuses on the inhibition processes of Mpro with natural phenolic compounds found in Cacao. A recent experimental study supports that phenolic compounds in cacao have inhibitory effects against Mpro activities. We began by exploring the potential inhibitory activities of trans-clovamide, a naturally occurring caffeoyl conjugate that is found in the phenolic fraction of Theobroma Cacao L. Here, we propose inhibitory mechanisms by which clovamide acts as a Mpro inhibitor as it scavenges reactive oxygen species in the body. We use molecular docking and annealing-based molecular dynamics simulations to study the interactions between Mpro catalytic site residues and clovamide and its analogues. Our molecular modelling studies provide mechanistic insights of clovamide inhibition of Mpro, and indicate that clovamide may be a promising candidate as a drug lead molecule for COVID-19 treatments.

Mechanistic insights on the inhibition of SARS-CoV-2 Mpro by natural phenolic compounds from Theobroma cacao L.: In Silico studies by molecular docking and molecular dynamics simulations

ACS Spring Meeting 2021

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