In Silico Structural Study, Design and Efficacy Evaluation of Fluoro Isoxazolidine Derivatives as Potential...

The decreasing efficacy of traditional antibiotics due to increasing antimicrobial resistance represents an urgent challenge. This study presents a comprehensive in silico study of the antibacterial potential of novel fluoroisoxazolidine derivatives, complementing Chakraborty in vitro results to assess their antimicrobial efficacy. Using computational modeling, including density functional theory (DFT), ADMET analysis, and molecular docking simulations, we explore their electronic properties, biological interactions, and pharmacokinetic profiles. In particular, we provide their optimized molecular structures and NMR spectra (¹H and ¹³C). We also analyzed their electrostatic potential maps to visualize the charge distributions on these fluoroisoxazolidine compounds, identifying electrophilic and nucleophilic sites. This predicts functional group reactivity and protein-ligand interactions, useful for drug design. Additionally, we perform various analyses (frontier molecular orbital, chemical potential, and hardness), which confirm the stability of these compounds and indicate strong interactions with the biological target. Furthermore, molecular docking simulations reveal strong binding affinities for two compounds of the selected series, towards methicillin-resistant Staphylococcus aureus (PDB: 2 × 3 F), with calculated binding energies up to -9.2 kcal/mol. Further molecular dynamics simulations confirm their favorable interaction with this protein and their possible inhibition of this protein, in accordance with the docking results and in strong agreement with the in vitro results. Furthermore, ADMET data show good intestinal absorption characteristics, with a percentage above 90%. The absence of skin sensitization reveals that these compounds are unlikely to cause allergic reactions or skin irritation upon topical exposure. Finally, we identify potential candidates with potent antibacterial activity, exhibiting favorable safety profiles and acceptable pharmacokinetic properties, making them promising development of new antibiotics after in vivo testing.