In silico interaction analysis of selected natural compounds with bacteriophage-encoded hyaluronate lyase from...

The rising antibiotic resistance of Streptococcus pyogenes necessitates alternative anti-virulence strategies. Bacteriophage-encoded hyaluronate lyase (HylP2), a key virulence factor that promotes bacterial dissemination by degrading host extracellular matrix components, represents an attractive therapeutic target.

In this study, an integrated in silico approach was employed to identify potential HylP2 inhibitors from a library of 118 bioactive natural compounds. Following protocol validation through redocking of ascorbic acid (RMSD = 1.897 Å), virtual screening, ADMET prediction, molecular dynamics (MD) simulations, and per-residue energy decomposition analyses were performed.

Violacein (-7.7 kcal/mol), sulfangolid C (-7.427 kcal/mol), chlorotonil A (-7.4 kcal/mol), xiamycin (-7.3 kcal/mol), and kulkenon (-7.1 kcal/ mol) were identified as the most potent binders. ADMET analysis confirmed that these leads possess favorable pharmacokinetic properties and compliance with Lipinski's Rule of Five. Subsequent 100-ns molecular dynamics (MD) simulations and per-residue energy decomposition revealed that violacein, xiamycin, and kulkenon formed stable, compact complexes by "trapping" catalytic residues Arg279 and Tyr264.

These findings suggest that these natural product scaffolds are promising anti-virulence leads that may limit S. pyogenes tissue invasion while minimizing selective pressure for resistance development.