In Silico Evaluation of a Novel Biphenyl-Triazole Derivative as a Potential CYP51 Inhibitor: A Molecular Docking Study

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Azole antifungals act by inhibiting fungal lanosterol 14α-demethylase (CYP51), and the spread of azole resistance, particularly among non-albicans Candida species, makes new CYP51-targeted compounds necessary. Here, the novel biphenyl–triazole derivative 1-(2-([1,1′-biphenyl]-4-yl)-2-(benzyloxy)ethyl)-1H-1,2,4-triazole (BTE1), designed to combine a heme-coordinating triazole ring with a hydrophobic biphenyl substituent, was evaluated computationally. BTE1 was built and energy-minimised with the MM2 force field (ChemOffice Professional 15.0), and its R- and S-enantiomers were docked with AutoDock 4.2.6 (50 runs per ligand) into Candida albicans CYP51 (PDB: 5FSA, 5V5Z) and, as a comparative model, Mycobacterium tuberculosis CYP51 (1EA1); the co-crystallised azoles fluconazole, itraconazole and posaconazole served as references, and redocking validated the protocol, reproducing the experimental poses with RMSD values of 0.99, 1.56 and 1.44 Å for fluconazole/1EA1, itraconazole/5V5Z and posaconazole/5FSA, respectively. Physicochemical, drug-likeness and ADME properties were predicted with SwissADME. Both enantiomers occupied the active site and interacted with the heme group, with S-BTE1 consistently giving slightly more favourable scores and estimated Ki values than R-BTE1 in all three models. The best predicted affinity was obtained against 5V5Z (−10.33 kcal/mol; estimated Ki 27.01 nM for S-BTE1), whereas in 1EA1 R- and S-BTE1 scored −10.14 and −10.24 kcal/mol versus −7.07 kcal/mol for fluconazole. π–π, π–cation and hydrogen-bonding interactions with key active-site residues and the heme were observed, and the predicted ADME profile complied with commonly applied drug-likeness criteria. These findings identify BTE1, particularly its S-enantiomer, as a promising scaffold, but they are purely predictive; enzymatic and antifungal assays are required to confirm CYP51 inhibition and biological activity.