Authors : Pramod Gajbhiye; Rutuja Thakare

Volume/Issue : Volume 11 - 2026, Issue 3 - March

Google Scholar : https://tinyurl.com/5cjb9ny6

Scribd : https://tinyurl.com/yh4ytuxe

DOI : https://doi.org/10.38124/ijisrt/26mar951

Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.

Abstract : Inhibitors of 14α-Demethylase (CYP51) are often used as antifungal therapies. This work included molecular docking of several imidazole-based compounds with CYP51 inhibitory capabilities, followed by QSAR analysis to determine the optimal physicochemical characteristics of potential CYP51 inhibitors. 1. Imidazoles of interest were constructed using HyperChem, thereafter undergoing conformational analysis using a semiempirical approach, followed by the use of the PM3 technique. "Docking was conducted with all compounds with AutoDock. CYP51 represents a compelling class of P450 enzymes for fundamental study and serves as a pivotal mechanism for several useful pharmaceuticals.'' This study will provide an update on the CYP51 family members, their physiological functions, natural substrates, substrate preferences, and potential manipulation in laboratory experiments. We have presented evidence that conserved CYP51 amino acid sequences serve as a hallmark of CYP51. Two key patterns in the evolution of CYP51 are examined, along with a synopsis of the significant efforts in CYP51 inhibition. [3, 4] The fungal cytochrome P450 enzyme sterol 14 alpha-demethylase (SDM) is an essential enzyme in the ergosterol biosynthesis pathway. The binding of azoles to the active site of SDM results in the depletion of ergosterol in cells [5].

Keywords : 14α-Demethylase, Molecular Docking, Thiadizoles Derivatives, Ligand-Target Interaction, ADME Prediction.

References :

1. DAVOOD, ASGHAR and IMAN, MARYAM (2013) ‘Molecular docking and QSAR study on imidazole derivatives as 14 /alpha -demethylase inhibitors,’ Turkish Journal of Chemistry: Vol. 37: No. 1, Article 9. https://doi.org/10.3906/kim-1204-8
2. Galina I. Lepesheva and Michael R. Waterman Sterol 14α-Demethylase Cytochrome P450 (CYP51), a P450 in all Biological Kingdoms Biochim Biophys Acta. 2007 Mar; 1770(3): 467–477.
3. Katharina Rosam, Brian C. Monk and Michaela Lackner Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens. Fungi 2021, 7, 1. https://doi.org/10.3390/jof701000
4. L.R. Peyton, S. Gallagher and M. Hashemzadeh TRIAZOLE ANTIFUNGALS Article in Drugs of today (Barcelona, Spain: 1998) · December 2015 https://www.researchgate.net/publication/297049099
5. R. Davies a 1, Franziska Wohlgemuth a 1, Taran Young a, Joseph Violet a, Matthew Dickinson b, Evolving challenges and strategies for fungal control in the food supply chain Volume 36, June 2021, Pages 15-26
6. Tatiana Y Hargrove 1, Laura Friggeri 1, Zdzislaw Wawrzak 2, Aidong Qi 1, Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis 10.1074/jbc.M117.778308. Epub 2017 Mar 3.
7. Edmond, M. B.; Wallace, S. E.; McClish, D. K.; Pfaller, M. A.; Jones, R. N.; Wenzel, R. P. Clin. Infect. Dis. 1999, 29, 239–244.
8. Steenbergen, J. N.; Casadevall, A. J. Clin. Microbiol. 2000, 38, 1974–1976.
9. Holger B Deising 1, Sven Reimann, Sérgio F Pascholati Mechanisms and significance of fungicide resistance 2008 Apr;39(2):286-95. 10.1590/S1517-
10. Morris, G. M.; Goodsell, D. S.; Pique, M. E.; Lindstrom, W. L.; Huey, R.; Forli, S.; Hart, W. E.; Halliday, S.; Belew, R.; Olson, A. J. AutoDock 4.2 with AutoDockTools. http://autodock.scripps.edu/faqs-help/manual/autodock-4-2-user-guide/AutoDock4.2 UserGuide.pdf, 2009
11. Todeschini, R. Milano Chemometrics and QSAR Group, http://michem.disat.unimib.it/, e-dragon (http://www.vcclab.org/ lab/edragon), 2008
12. Wang, W., Sheng, C., Che, X. et al. Discovery of highly potent novel antifungal azoles by structure-based rational design. Bioorg Med Chem Lett 2009, 19(20): 5965-
13. Podust, L.M., Poulos, T.L., Waterman, M.R. Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc Natl Acad Sci U S A 2001, 98(6): 3068-7
14. Richardson, K., Cooper, K., Marriott, M.S., Tarbit, M.H., Troke, P.F., Whittle, P.J. Discovery of fluconazole, a novel antifungal agent. Rev Infect Dis 1990, 12(Suppl. 3): S267-7
15. Sobue, S., Tan, K., Layton, G., Eve, M., Sanderson, J.B. Pharmacokinetics of fosfluconazole and fluconazole following multiple intravenous administration of fosfluconazole in healthy male volunteers. Br J Clin Pharmacol 2004, 58(1):
16. Pasqualotto, A.C., Denning, D.W. New and emerging treatments for fungal infections. J Antimicrob Chemother 2008, 61((Suppl. 1)): i19-30
17. Ramos, G., Cuenca-Estrella, M., Monzon, A., RodriguezTudela, J.L. In-vitro comparative activity of UR-9825, itraconazole and fluconazole against clinical isolates of Candida spp. J Antimicrob Chemother 1999, 44(2): 283-6
18. Dietz, A.J., Barnard, J.C., van Rossem, K. A randomized, double-blind, multiple-dose, placebo-controlled, dose escalation study with a 3-cohort parallel group design to investigate the tolerability and pharmacokinetics of albaconazole in healthy subjects. Clin Pharmacol Drug Dev 2014, 3: 25-
19. Nafiz Öncü Can,Ulviye Acar Çevik,Begüm Nurpelin Sağlık,Serkan Levent,Büşra Korkut Synthesis, Molecular Docking Studies, and Antifungal Activity Evaluation of New Benzimidazole-Triazoles as Potential Lanosterol 14α-Demethylase Inhibitors Volume 2017 | Article ID 9387102 | https://doi.org/10.1155/2017/9387102
20. Hata, K., Kimura, J., Miki, H., Toyosawa, T., Nakamura, T., Katsu, K. In vitro and in vivo antifungal activities of ER30346, a novel oral triazole with a broad antifungal spectrum. Antimicrob Agents Chemother 199
21. Bibek Pati,* Subhasis Banerjee Molecular Docking Based Virtual Design of Polysubstituted Triazoles as Cytochrome P-450 14-Alpha-Sterol Demethylase (Cyp51) Inhibitor Journal of PharmaSciTech 2012; 1(2):46-51
22. Alvar, J.; Velez, I.D.; Bern, C.; Herrero, M.; Desjeux, P.; Cano, J.; Jannin, J.; den Boer, M.; WHO Leishmaniasis Control Team. Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 2012, 7, e35671. [CrossRef] [PubMed]
23. Hargrove, T.Y.; Wawrzak, Z.; Liu, J.; Waterman, M.R.; Nes, W.D.; Lepesheva, G.I. Structural complex of sterol 14α-demethylase (cyp51) with 14α-methylenecyclopropyl-∆7-24, 25-dihydrolanosterol. J. Lipid Res. 2012, 53, 311–320. [CrossRef] [PubMed]
24. Parker, J.E.; Warrilow, A.G.; Price, C.L.; Mullins, J.G.; Kelly, D.E.; Kelly, S.L. Resistance to antifungals that target cyp51. J. Chem. Biol. 2014, 7, 143–161.
25. Colovos, C.; Yeates, T.O. Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Sci. 1993, 2, 1511–1519
26. Arnautova, Y.A.; Abagyan, R.A.; Totrov, M. Development of a new physics-based internal coordinate mechanics force field and its application to protein loop modeling. Proteins 2011, 79, 477–498
27. Snelders, E.; Karawajczyk, A.; Schaftenaar, G.; Verweij, P.E.; Melchers, W.J. Azole resistance profile of amino acid changes in Aspergillus fumigatus cyp51a based on protein homology modeling. Antimicrob. Agents Chemother. 2010, 54, 2425–2430.
28. Phillips, J.C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R.D.; Kale, L.; ‘Schulten, K. Scalable molecular dynamics with namd. J. Comput. Chem. 2005, 26, 1781–1802.’