Simulating New Fusidic Acid Derivatives to Target Gram-Positive Bacteria by Using Computational Methods

Abstract

Gram-positive bacteria represent a significant threat due to their resistance to conventional antibiotics. This study employs computational methods to investigate fusidic acid (FA) derivatives (1–24) as potential antibiotics against Gram-positive bacteria. Techniques such as density functional theory calculations, molecular docking, and molecular dynamics simulations were utilized to evaluate ligand interactions with target proteins Staphylococcus aureus (S. aureus) elongation factor G (fusA) (2XEX), fusidic acid resistance protein (fusB) (4ADN), and fusidic acid resistance protein (fusC) (2YB5), comparing them to established antibiotics (ceftobiprole, linezolid, vancomycin). Notably, ligand 16 demonstrated a remarkable binding affinity to the S. aureus elongation factor G protein (−8.7 kcal mol⁻¹), closely aligning with both in vitro and in vivo results and outperforming fusidic acid and reference drugs. In silico methods (SwissADME, AdmetSAR, Molinspiration, Molsoft) were used to assess pharmacokinetics and drug-likeness. Molecular dynamics (MD) simulations confirmed superior S. aureus elongation factor G stability for ligands fusidic acid 1, (Z)-2-((3R,4S,8S,9R,10S,11R,13S,14S,16S)-16-acetoxy-3,11-dihydroxy-4,8,10,14-tetramethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-ylidene)-5-cyclohexylidene- pentanoic acid (14), (Z)-2-((3R,4S,8S,9R,10S,11R,13S, 14S,16S)-16-acetoxy-3,11-dihydroxy-4,8,10,14-tetramethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-ylidene)-5cyclohexylidenepentanoic acid (16), and (Z)-2-((3R,4S,8S,9R,10S,11R,13S,14S,16S)-16-acetoxy-3,11-dihydroxy-4,8,10,14-tetramethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-ylidene)-5-cyclopentylidenepentanoic acid (17), with ligand 16 exhibiting exceptional stability across various temperatures, especially at human body temperature (310 K). Further molecular dynamics simulations of ligand 16 validated its robust stability and potential to disrupt S. aureus elongation factor G, supporting the docking results and showing strong consistency with in vitro and in vivo findings. Consequently, ligand 16 emerges as a promising candidate for further development as an anti-Gram-positive bacterial drug, pending validation through rigorous clinical trials.