Computational Identification of Paederia foetida Linn. Phytochemicals as Potential Inhibitors of Staphylococcus aureus Peptide Deformylase

Staphylococcus aureus is a common cause of foodborne gastroenteritis and poses a growing public health concern due to its heat-stable enterotoxins and increasing antimicrobial resistance. In this study, an integrated in silico strategy was employed to investigate phytochemicals from Paederia foetida Linn. as potential inhibitors of S. aureus peptide deformylase (PDF), an essential bacterial enzyme absent in humans. LC-MS profiling of the hexane leaf extract tentatively annotated 139 phytochemicals, of which 110 structurally suitable compounds were selected for molecular docking. From these, the top 12 compounds possessing functional groups capable of forming stabilizing interactions within the catalytic pocket of PDF were shortlisted for further evaluation. Among them, the four best-performing compounds were 12-Epi-Scalaradial (− 8.7 ± 0.10 kcal/mol), Obliquine (− 8.6 ± 0.10 kcal/mol), Anisotine (− 8.5 ± 0.10 kcal/mol), and Deoxytubulosine (− 8.4 ± 0.10 kcal/mol), all of which demonstrated stronger predicted binding affinities than the native ligand MDB (− 8.2 ± 0.10 kcal/mol).

To further assess the stability and binding behavior of these complexes, six independent 100 ns molecular dynamics simulations were performed. 12-Epi-Scalaradial exhibited a rigid and persistent binding pose stabilized by interactions with Gly110 and Leu112, suggesting a conformational restriction mechanism. In comparison, Obliquine and Deoxytubulosine maintained stable yet flexible interactions with key active-site residues. MM-PBSA analysis identified Deoxytubulosine (− 66 kJ/mol) and Obliquine (− 61 kJ/mol) as the most energetically favorable binders, whereas 12-Epi-Scalaradial appeared to contribute primarily to stabilization of the conformational dynamics of PDF. SwissADME predictions indicated favorable drug-likeness and gastrointestinal absorption for the prioritized compounds, although their limited aqueous solubility may require further formulation optimization. Overall, Deoxytubulosine and Obliquine emerged as promising natural candidates for further investigation as potential inhibitors of S. aureus PDF, which require experimental validation.