In silico screening of potential inhibitors of Staphylococcus aureus FabI

Abstract

This study aimed to identify novel potential inhibitors of the FabI enzyme (enoyl-acyl carrier protein reductase) from Staphylococcus aureus through the integration of pharmacophore modelling, molecular docking, and molecular dynamics (MD) simulations. Based on the interaction between FabI and the reference compound AFN-1252 (N-(2-methylphenyl)-5-methyl-3-phenyl-4-isoxazolecarboxamide), a pharmacophore model consisting of five molecular features was constructed and used to screen 13 million compounds from the ZINC library. A total of 2,216 compounds satisfying the model criteria (RMSD≤1 Å) were subjected to molecular docking using AutoDock Vina while retaining the NADPH cofactor (nicotinamide adenine dinucleotide phosphate). 13 compounds showed docking scores equal to or lower than that of AFN-1252 (-11.2 kcal/mol), among which four compounds that simultaneously interacted with NADPH and key amino acid residues were selected for MD simulations and binding energy calculation using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The results showed that these molecules maintained interactions with amino acid residues and NADPH. In particular, ligand 760 exhibited high stability and a binding energy of -18.99 kcal/mol, indicating its potential for further development as a FabI inhibitor with antibacterial activity.