Bio evaluation of 1,2,4-triazole–thiopyrimidine hybrids as potential lanosterol 14-alpha demethylase inhibitors using water aware docking and molecular dynamics simulation approaches

This study employed an integrated computational approach to identify novel 1,2,4-triazole–thiopyrimidine hybrids as potential inhibitors of lanosterol 14-α demethylase (CYP51), a key enzyme in fungal ergosterol biosynthesis. Nineteen compounds were designed and optimized using density functional theory (DFT) to evaluate their electronic properties and reactivity. Induced-fit water-aware molecular docking revealed binding affinities ranging from − 5.53 to − 7.98 kcal/mol, with Compounds 15 and Compound 16 exhibiting superior interactions compared to the reference inhibitor. Detailed interaction analysis highlighted the critical roles of key residues such as CYS470, LYS151, and HIS468, alongside structured water molecules in stabilizing ligand binding. Molecular dynamics simulations over 200 ns further confirmed the stability and conformational behavior of selected complexes. Principal component analysis (PCA), RMSD, RMSF, and radius of gyration (Rg) analyses demonstrated that CPD15–5EQB exhibited the highest structural compactness and stability, while CPD16 showed greater flexibility. Moreover, the results indicate that Compounds 15 and 16 possess strong inhibitory potential, with compound 15 displaying superior stability and binding efficiency. These findings provide a robust computational foundation for the development of novel antifungal agents targeting CYP51.