Computational evaluation of novel hydantoin hydrazone hybrids as potential antimicrobial candidates against DNA gyrase and CYP51

Abstract Hydantoin hydrazone hybrids, including compounds 2 , 3a–d , 4a–b , 5a–b , and 6 , were computationally investigated as potential dual-target antimicrobial candidates using an integrated workflow comprising density functional theory (DFT), molecular docking, molecular dynamics (MD) simulations, and MM-PBSA binding free energy analysis. DFT calculations at the APFD/6-311 + + G(d, p) level in the gas phase and DMSO using the SMD solvation model revealed favorable solvation free energies ranging from − 94.84 to − 121.45 kJ/mol. Solvation increased the dipole moments and polarizabilities of the investigated compounds, with 3c and 3b showing the largest dipole moments and 5b exhibiting the highest polarizability. Compound 4a displayed the lowest chemical hardness, highest softness, and greatest electrophilicity in DMSO, indicating enhanced intrinsic electronic reactivity. FMO, MESP, Fukui function, QTAIM, and NCI/RDG analysis further characterized solvent-dependent charge redistribution and persistent intramolecular noncovalent interactions that may contribute to conformational preorganization. Molecular docking against bacterial DNA gyrase subunit B (PDB ID: 3TTZ) and fungal lanosterol 14α-demethylase (CYP51; PDB ID: 5V5Z) yielded predicted binding affinities ranging from − 7.292 to − 9.032 kcal/mol and − 8.114 to − 11.023 kcal/mol, respectively. Among the investigated compounds, oxindole derivatives 5a and 5b exhibited favorable docking profiles against both targets. Short-timescale 10 ns MD simulations were subsequently used to assess the dynamic behavior of selected protein–ligand complexes, while MM-PBSA analysis provided comparative estimates of binding energetics, identifying 5b and 3b as the most favorable DNA gyrase binders and 3a and 5a as the most favorable CYP51 binders. Overall, compounds 5a and 5b emerged as promising candidates based on their combined docking and energetic profiles. However, these findings represent computational predictions and require experimental validation. Future studies involving longer independent MD simulations, validated target-specific force-field parameters, and rigorous free-energy methodologies, together with experimental DNA gyrase and CYP51 inhibition assays, are warranted to further evaluate and validate the predicted binding profiles.