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<p><i>Pseudomonas aeruginosa</i>, a multidrug-resistant nosocomial pathogen, necessitates the identification of alternative antivirulence strategies against this organism. Xanthones, which have demonstrated anti-quorum sensing (QS) activity demonstrated in biosensor assays, represent promising candidates as LasR inhibitors. This study aimed to computationally evaluate xanthones as potential LasR inhibitors, focusing on QS inhibition through blockade of the autoinducer-binding domain and the predicted consequent reduction of virulence factor expression. Nineteen structurally diverse xanthones were retrieved from PubChem (molecular weight: 350–400&#xa0;g/mol), including prenylated, hydroxylated and methoxylated derivatives, to ensure chemical diversity and computational feasibility in assessing potential QS inhibitors. N-3-oxododecanoyl-L-homoserine lactone (C<sub>12</sub>-AHL) was used as the reference ligand. Molecular docking analyses yielded binding free energies ranging from -6.2 to -12.3&#xa0;kcal/mol. The four top-ranked compounds (GH, TDX, 1_6_7_TD2HPMX and 1_5_6_TD2HPMX) were further evaluated for pharmacokinetics and oral toxicity using ProTox-II and predicted median lethal dose (DL<sub>50</sub>) values in mice. Although some xanthones slightly exceeded the lipophilicity threshold defined by Muegge’s rule, GH and TDX exhibited favorable ADME profiles and acceptable toxicity predictions, supporting their selection as suitable candidates for potential topical formulations against <i>P. aeruginosa</i> infections. Interaction analyses of the xanthone-LasR complexes revealed stable contacts with key residues Tyr56, Ala50, Ser129, Ala127, Leu40, Leu125 and Val126 within the autoinducer-binding domain. Notably, the binding mechanisms differed from that of the natural ligand C<sub>12</sub>-AHL. Molecular dynamics (MD) simulations (100&#xa0;ns) and MM/GBSA calculations confirmed the stability of the complexes, with average binding free energies ranging of -11.19 ± 0.479 and -13.61 ± 0.114&#xa0;kcal/mol. Overall, GH and TDX emerged as the most promising candidates for further experimental validation as potential topical anti-QS to attenuate <i>P. aeruginosa</i> virulence.</p>

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Computational evaluation of xanthone derivative as potential LasR inhibitors in Pseudomonas aeruginosa

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Esmeralda Escobar Muciño

摘要

Pseudomonas aeruginosa, a multidrug-resistant nosocomial pathogen, necessitates the identification of alternative antivirulence strategies against this organism. Xanthones, which have demonstrated anti-quorum sensing (QS) activity demonstrated in biosensor assays, represent promising candidates as LasR inhibitors. This study aimed to computationally evaluate xanthones as potential LasR inhibitors, focusing on QS inhibition through blockade of the autoinducer-binding domain and the predicted consequent reduction of virulence factor expression. Nineteen structurally diverse xanthones were retrieved from PubChem (molecular weight: 350–400 g/mol), including prenylated, hydroxylated and methoxylated derivatives, to ensure chemical diversity and computational feasibility in assessing potential QS inhibitors. N-3-oxododecanoyl-L-homoserine lactone (C12-AHL) was used as the reference ligand. Molecular docking analyses yielded binding free energies ranging from -6.2 to -12.3 kcal/mol. The four top-ranked compounds (GH, TDX, 1_6_7_TD2HPMX and 1_5_6_TD2HPMX) were further evaluated for pharmacokinetics and oral toxicity using ProTox-II and predicted median lethal dose (DL50) values in mice. Although some xanthones slightly exceeded the lipophilicity threshold defined by Muegge’s rule, GH and TDX exhibited favorable ADME profiles and acceptable toxicity predictions, supporting their selection as suitable candidates for potential topical formulations against P. aeruginosa infections. Interaction analyses of the xanthone-LasR complexes revealed stable contacts with key residues Tyr56, Ala50, Ser129, Ala127, Leu40, Leu125 and Val126 within the autoinducer-binding domain. Notably, the binding mechanisms differed from that of the natural ligand C12-AHL. Molecular dynamics (MD) simulations (100 ns) and MM/GBSA calculations confirmed the stability of the complexes, with average binding free energies ranging of -11.19 ± 0.479 and -13.61 ± 0.114 kcal/mol. Overall, GH and TDX emerged as the most promising candidates for further experimental validation as potential topical anti-QS to attenuate P. aeruginosa virulence.