Allosteric Interactions of Flavonoids with ACE2 and Potential Implications for COVID-19: Computational Insights, Metabolic and Mitochondrial Effects of Rutin in A549 Cells
Abstract
There has been a compelling need to identify new therapeutic targets and agents owing to the increasing complexity of disease mechanisms. Angiotensin-converting enzyme 2 (ACE2), the primary host receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, plays a crucial role in the pathophysiology of COVID-19, making ACE2 a potential biological target. Identification of small molecules that can interact with ACE2 may offer insights into a host-targeted approach relevant to viral entry and ACE2-associated cellular pathways. The study evaluated allosteric interactions of selected flavonoids with ACE2, the cytotoxicity and metabolic effects of the promising candidate in A549 cells through computational and in vitro methods. Molecular docking identified flavonoid binding to ACE2, followed by a 120 ns molecular dynamics (MD) simulation to characterize the stability and dynamic behaviour of ACE2-flavonoid complexes. MM/GBSA binding free energy calculations and per residue energy decomposition were performed to identify key interactions stabilizing ligand binding. The in silico analyses showed ARG255, PRO328, GLU357, GLU384, GLU388, and ARG500 as the key allosteric residues contributing to ACE2-flavonoid complex stability. Rutin exhibited the most favourable binding affinity, followed by isoquercetin. Based on computational findings, rutin was selected for evaluation in A549 cells to assess cytotoxicity, metabolic and mitochondrial effects using MTT assay, ATP…
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