<i>In silico</i> screening of UM-C162 and UM-4E as potential inhibitors of  <i>Staphylococcus aureus</i> virulence factors

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) is one of the main pathogens responsible for both hospital-acquired and community-acquired infections. The rising prevalence of antibiotic resistance has shifted research focus towards alternative therapeutic strategies particularly anti-virulence agents. Unlike conventional antibiotics, these compounds target bacterial virulence factors without exerting bactericidal pressure, thereby reducing the risk of resistance development. Small-molecule inhibitors such as UM-4E and UM-C162 have emerged as promising candidates for this approach. This study applied molecular docking and molecular dynamics (MD) simulations to evaluate the inhibitory potential of UM-4E and UM-C162 against key virulence factors of <i>S. aureus</i>, namely alpha toxin (Hla), sortase A (SrtA), accessory gene regulator A (AgrA), and V8 protease (SspA). Docking analysis revealed that UM-4E consistently achieved the lowest binding energy scores across all receptors, followed by UM-C162. Subsequently, 100 ns MD simulations were performed for UM-4E-Hla and UM-C162-Hla complexes, showing stable and compact conformations throughout. Residue decomposition analysis highlighted VAL149 and THR109 as major contributors in UM-4E-Hla interactions, while PRO151, ILE107, and VAL149 played key roles in UM-C162-Hla. Overall, UM-4E demonstrated stronger binding affinity, stability, and residue-level interactions, suggesting its potential as a preferential Hla inhibitor. These computational findings provide a strong computational basis but warrant further validation through <i>in vitro</i> assays.