The study used computational analysis to screen 118 natural compounds as potential inhibitors of hyaluronate lyase HylP2, a key bacteriophage virulence factor from Streptococcus pyogenes that degrades the host's extracellular matrix and promotes bacterial spread. They verified the protocol by re-docking ascorbic acid with an RMSD of 1.897 Å. Virtual screening, ADMET prediction and molecular dynamics simulations identified violacein (-7.3 kcal/mol) and culkenone (-7.1 kcal/mol) as the strongest binding compounds. These compounds satisfy Lipinski's rule of five and have favorable pharmacokinetic properties. Hundred-nanosecond MD simulations showed that violacein, xiamycin, and culkenone formed stable complexes by trapping the catalytic residues Arg279 and Tyr264. The results suggest the potential of these compounds as alternative anti-virulence strategies against antibiotic resistance.