A hybrid machine learning and molecular dynamic simulation approaches for identifying FtsZ inhibitors in Staphylococcus aureus

The development of antibiotics with novel mechanisms of action is required due to the significant hazard to public health posed by the global increase in multidrug-resistant (MDR) Staphylococcus aureus infections. FtsZ, a tubulin-like GTPase that is essential for bacterial cytokinesis and is absent in human cells, is a highly selective antibacterial target. A comprehensive in silico methodology was implemented in this study to identify natural product-based inhibitors that target the FtsZ protein in S. aureus . Lipinski's Rule of Five was employed to curate and refine a library of natural compounds in order to identify drug-like candidates. These were subjected to molecular docking, which yielded 1070 compounds with strong binding affinities (<−6 kcal/mol). Additional screening was conducted using PSICHIC, a machine learning-based predictor of protein-ligand interaction. According to ADMET analysis, these compounds exhibit favourable pharmacokinetic profiles, including low toxicity and excellent oral bioavailability. In order to evaluate molecular stability, polarity, and reactivity, density functional theory (DFT) calculations were implemented, resulting in the identification of Hit 1, Hit 2, and Hit 3 as the preferred candidates. The structural stability and robust interaction of Hit 1 within the FtsZ binding site were confirmed by molecular dynamics (MD) simulations that lasted for 300 ns. The RMSD, hydrogen bonding, and solvent-accessible surface area (SASA) profiles were consistent. Hit 1's strong binding potential was confirmed by MM/GBSA binding free energy calculations, which revealed a ΔG of −38.82 kcal/mol, which is comparable to the known inhibitor ZI6 (−43.98 kcal/mol). Compound Hit 1 has shown to be an effective and stable inhibitor of FtsZ, serving as a promising candidate for the development of novel antibacterial medicines targeting MDR S. aureus . These findings require further in-vitro and in-vivo investigations to empirically validate the compound's medicinal potential and efficacy.