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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. [ABSTRACT FROM AUTHOR]

The rising antimicrobial resistance crisis has diminished the effectiveness of traditional antibiotics against pathogenic bacteria. This study addresses this urgent challenge by exploring the antibacterial potential of novel quinolone derivatives (1–33). Using computational in silico modeling to simulate biological interactions, we aimed to identify candidates with potent antibacterial activity. A total of 33 quinolone derivatives were assessed for their physicochemical properties and effectiveness against a range of clinically relevant pathogens, including methicillin‐resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, Streptococcus pneumoniae, and Enterococcus faecalis. Molecular docking studies identified compounds 28, 29, 32, and 33 as having notable binding affinities, particularly against MRSA. Further molecular dynamics simulations of compound 29 confirmed its favorable stability and potential for disrupting MRSA, reinforcing the docking results and showing strong alignment with in vitro findings. These findings position compound 29 as a promising lead for developing alternative MRSA therapies and underscore the need for further in vivo studies to evaluate its therapeutic potential. [ABSTRACT FROM AUTHOR]

This investigation employed computational methodologies to assess the therapeutic potential of derivatives (1–16) of pyridoxal isonicotinoyl hydrazone (PIH) as potential treatments for tuberculosis. Various computational techniques, including molecular dynamics simulation, molecular docking, density functional theory, and global chemical descriptors, were employed to analyze the interactions between the ligands and target proteins. Docking results indicated that ligands 6, 7, 8, and rifampin exhibited binding affinities of −8.4, −7.4, −9.2, and − 7.2 kcal mol−1, respectively, against mycobacterium tuberculosis enoyl acyl carrier protein reductase (INHA), with ligand 8 demonstrating superior inhibition. Molecular dynamics (MD) simulations were utilized to assess the stability of protein‐ligand interactions. Remarkably, the Root Mean Square Deviation (RMSD) of the INHA‐ligand 8 complex remained minimal, with peak values at.40,.56,.37, and.50 nm at temperatures of 300, 305, 310, and 320 K, respectively. This suggests superior stability compared to the reference drug rifampin and INHA complex, which exhibited an RMSD range of.2 to.8 nm at 300 K. Furthermore, analysis using Frontier Molecular Orbital (FMO) revealed that the Egap value of ligand 8 (4.407 eV) is lower than all the reference drugs except rifampin. This comprehensive theoretical analysis positions ligand 8 as a promising candidate for anti‐tuberculosis drug development, underscoring the need for further exploration through in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]