Discovery of Galloyl–Flavonoid Conjugates as SARS-CoV-2 3CLpro Inhibitors: Understanding Binding Interactions Through Computational Approaches

TL;DR

Researchers discovered that adding a galloyl group to flavonoids significantly boosts their ability to inhibit a key SARS-CoV-2 enzyme, offering a new approach for antiviral drug development.

Contribution

The study introduces galloyl-flavonoid conjugates as potent SARS-CoV-2 3CLpro inhibitors, identified through computational and experimental methods.

Findings

Adding a galloyl moiety to flavonoids increased anti-proteolytic activity up to 23-fold against SARS-CoV-2 3CLpro.

7-O-galloyl-DMC showed the highest anti-proteolytic activity in enzymatic assays.

Molecular dynamics simulations revealed hydrogen bonding and π-interactions between galloyl groups and 3CLpro residues Thr26 and Leu27.

Abstract

The emergence of SARS-CoV-2 in 2019 posed significant global public health challenges. One of the most promising targets for novel antiviral drug development is the SARS-CoV-2 main protease (3CLpro). In this study, fragment molecular orbital (FMO) calculations were conducted to provide guidance for the structural modification of natural flavonoids, identifying the pyrogallol moiety as a key candidate. Natural flavonoids were chemically modified to generate 33 semi-synthetic derivatives through the introduction of various functional groups. Our findings revealed that the incorporation of a galloyl moiety significantly enhances anti-proteolytic activity against SARS-CoV-2 3CLpro, achieving up to a 23-fold increase compared to the activity of the parent compounds. Notably, 7-O-galloyl-DMC (40) exhibited the highest anti-proteolytic activity in an enzymatic assay. Additionally, molecular dynamics simulations provided atomic-level insights into the interactions between the galloyl moiety and 3CLpro. All galloylated flavonoid derivatives positioned their galloyl groups within the S1′ sub-pocket, facilitating hydrogen bonding and π-interactions, particularly with Thr26 and Leu27. These findings underscore the potential of the galloyl moiety as a crucial structural element for enhancing the binding affinity of flavonoids with inhibitory activity against SARS-CoV-2 3CLpro.

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