In Silico Evaluation of a Novel Biphenyl-Triazole Derivative as a Potential CYP51 Inhibitor: A Molecular Docking Study
Abstract
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.
Keywords
Azole antifungals, CYP51, molecular docking, biphenyl-triazole, antifungal resistance, in silico
Supporting Institution
This study was supported by the Research Foundation of ˙Inonu University (grant numbers: TUA-2026-4835), Inonu University, Malatya, Türkiye
Project Number
TUA-2026-4835
References
- Anandani G, Bhise M, Agarwal A. Invasive fungal infections and the management in immunocompromised conditions. Journal of Family Medicine and Primary Care. Temmuz 2025;14(7):2643-52. doi:10.4103/jfmpc.jfmpc_1582_24
- Lionakis MS, Drummond RA, Hohl TM. Immune responses to human fungal pathogens and therapeutic prospects. Nat Rev Immunol. Temmuz 2023;23(7):433-52. doi:10.1038/s41577-022-00826-w
- Schell WA, Jones AM, Garvey EP, Hoekstra WJ, Schotzinger RJ, Alexander BD. Fungal CYP51 Inhibitors VT-1161 and VT-1129 Exhibit Strong In Vitro Activity against Candida glabrata and C. krusei Isolates Clinically Resistant to Azole and Echinocandin Antifungal Compounds. Antimicrob Agents Chemother. Mart 2017;61(3):e01817-16. doi:10.1128/AAC.01817-16
- Lepesheva GI, Friggeri L, Waterman MR. CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology. Aralık 2018;145(14):1820-36. doi:10.1017/S0031182018000562
- Warrilow AG, Parker JE, Kelly DE, Kelly SL. Azole Affinity of Sterol 14α-Demethylase (CYP51) Enzymes from Candida albicans and Homo sapiens. Antimicrob Agents Chemother. Mart 2013;57(3):1352-60. doi:10.1128/AAC.02067-12
- De Petris A, Crestoni ME, Pirolli A, Rovira C, Iglesias-Fernández J, Chiavarino B, vd. Binding of azole drugs to heme: A combined MS/MS and computational approach. Polyhedron. Nisan 2015;90:245-51. doi:10.1016/j.poly.2015.02.011
- Esfahani A, Omran AN, Salehi Z, Shams-Ghahfarokhi M, Ghane M, Eybpoosh S, vd. Up-regulation of CDR1 and MDR1 efflux pump genes and fluconazole resistance are involved in recurrence in Candida albicans-induced vulvovaginal candidiasis. Diagnostic Microbiology and Infectious Disease. Mayıs 2024;109(1):116242. doi:10.1016/j.diagmicrobio.2024.116242
- Hoy SM. Oteseconazole: First Approval. Drugs. 2022;82(9):1017–1023. doi:10.1007/s40265-022-01734-y.
- Guedes-da-Silva FH, Batista DGJ, Da Silva CF, De Araújo JS, Pavão BP, Simões-Silva MR, vd. Antitrypanosomal Activity of Sterol 14α-Demethylase (CYP51) Inhibitors VNI and VFV in the Swiss Mouse Models of Chagas Disease Induced by the Trypanosoma cruzi Y Strain. Antimicrob Agents Chemother. Nisan 2017;61(4):e02098-16. doi:10.1128/AAC.02098-16
- Han G, Liu N, Li C, Tu J, Li Z, Sheng C. Discovery of Novel Fungal Lanosterol 14α-Demethylase (CYP51)/Histone Deacetylase Dual Inhibitors to Treat Azole-Resistant Candidiasis. J Med Chem. 28 Mayıs 2020;63(10):5341-59. doi:10.1021/acs.jmedchem.0c00102