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In silico exploration of natural xanthone derivatives as potential inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and cellular entry

ORCID
0000-0002-6151-7009
Affiliation
Department of Chemical Sciences University of Johannesburg P. O. Box 17011 Doornfontein Campus 2028 Johannesburg South Africa
Obakachi, Vincent A.;
ORCID
0000-0001-8337-9260
Affiliation
Institut für Chemie Universität Potsdam Karl-Liebknecht-Str. 24-25 D-14476 Potsdam-Golm Germany
Nchiozem-Ngnitedem, Vaderament-A.;
ORCID
0000-0002-3079-5989
Affiliation
Department of Chemical Sciences University of Johannesburg P. O. Box 17011 Doornfontein Campus 2028 Johannesburg South Africa
Govender, Krishna K.;
ORCID
0000-0002-3011-6675
Affiliation
Department of Chemical Sciences University of Johannesburg P. O. Box 17011 Doornfontein Campus 2028 Johannesburg South Africa
Govender, Penny P.

Abstract The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgent need for effective antiviral therapies, particularly against vaccine-resistant variants. This study investigates natural xanthone derivatives as potential inhibitors of the ACE2 receptor, a critical entry point for the virus. We computationally evaluated 91 xanthone compounds derived from Swertia chirayita , identifying two promising candidates: 8-O-[β-D-Xylopyranosyl-(1→6)-β-D-glucopyranosyl]-1,7-dihydroxy-3-methoxy xanthone (XAN71) and 8-O-[β-D-Xylopyranosyl-(1→6)-β-D-glucopyranosyl]-1-hydroxy-3,7-dimethoxy-xanthone (XAN72). Molecular docking and dynamics simulations (MDDS) were performed to assess their binding energy and stability within the ACE2 active site, comparing them to the reference inhibitor MLN-4067. The top six compounds were selected based on their docking performance, followed by Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations to quantify binding affinities. Additionally, molecular electrostatic potential (MEP) analysis was conducted to visualize electron density regions relevant to binding interactions. Our results demonstrate that XAN71 and XAN72 exhibit superior binding affinities of -70.97 and − 69.85 kcal/mol, respectively, outperforming MLN-4067 (-61.33 kcal/mol). MD simulations revealed stable interactions with key ACE2 residues, primarily through hydrogen bonds and hydrophobic contacts. The Molecular Electrostatic Potential(MEP) analysis further elucidated critical electron density regions that enhance binding stability. This study establishes XAN71 and XAN72 as viable candidates for ACE2 inhibition, providing a structural basis for their development as natural xanthone-based therapeutics against SARS-CoV-2. These findings highlight the potential of targeting ACE2 with natural compounds to combat COVID-19, particularly in light of emerging viral variants.

Highlights XAN71 and XAN72 exhibit stronger ACE2 binding than the reference inhibitor MLN-4067. XAN71 and XAN72 form unique and stable hydrogen bonds with ACE2 active site residues. Both ligands display stable RMSD values throughout 200 ns molecular dynamics simulations. Electrostatics and van der Waals interactions significantly enhance XAN71 and XAN72 binding. XAN72’s smaller HOMO-LUMO gap suggests higher reactivity compared to other compounds. Graphical abstract

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