PHYTOCHEMICALS AS POTENTIAL INHIBITORS OF LANOSTEROL 14 Α-DEMETHYLASE (CYP51) ENZYME: AN IN SILICO STUDY ON SIXTY MOLECULES
DOI:
https://doi.org/10.22159/ijap.2020.v12s4.40100Keywords:
Nil, Phytochemicals, Molecular docking, Candida albicans, Ergosterol synthesisAbstract
Lanosterol 14 α-demethylase (CYP51) is a key protein involved in ergosterol biosynthesis of Candida albicans and a crucial target for ergosterol synthesis inhibition. However, in the last two decades drug resistance is reported under clinical situations to most of the prescribed antifungal drugs like azole group of drugs. In this study, molecular docking of sixty plant molecules with Lanosterol 14 α-demethylase protein has been done. The homology modeling tool PHYRE2 was used to predict the structure of Lanosterol 14 α-demethylase. Predicted structure was used for docking studies with sixty plant molecules by using Autodock 1.5.6 cr2™. Among the sixty plant molecules, forty-seven were found to form hydrogen bond and the rest of the plant molecules did not form a hydrogen bond with Lanosterol 14 α-demethylase. Docking study of a library of sixty molecules revealed that 48 plant molecules showed an excellent and good binding affinity with predicted protein model Lanosterol 14 α-demethylase of Candida albicans. The binding residue comparison of docked molecules with that of Ketoconazole revealed, fourteen molecules have similar binding residue. These fourteen molecules may have a similar mode of action as that of Ketoconazole. These molecules should be screened and used to discover new antifungal therapeutic drugs.
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References
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2. Denning DW, Bromley MJ. How to bolster the antifungal pipeline. Science 2015;347:1414-6.
3. Bard M, Lees ND, Turi T. Sterol synthesis and viability of erg 11 (cytochrome P450 lanosterol demethylase) mutations in Saccharomyces cerevisiae and Candida albicans. Lipids 1993;28:963-7.
4. Ji H, Zhang W, Zhou Y. A three-dimensional model of lanosterol 14 ?-demethylase of Candida albicans and its interaction with azole antifungals. J Med Chem 2000;43:2493-12.
5. Lamb DC, Kelly DE, Venkateswarlu K. Generation of a complete, soluble, and catalytically active sterol 14?-demethylase?reductase complex. Biochemistry 1999;38:8733-8.
6. Trzaskos JM, Fischer RT, Favata MF. Mechanistic studies of lanosterol C-32 demethylation. Conditions which promote oxysterol intermediate accumulation during the demethylation process. J Bio Chem 1986;261:16937-42.
7. Aoyama Y, Yoshida Y, Sonoda Y. Deformylation of 32-oxo-24,25-dihydrolanosterol by the purified cytochrome P-45014DM (Lanosterol 14R-demethylase) from yeast evidence confirming the intermediate step of lanosterol 14R-demethylation. J Biol Chem 1989;264:18502-5.
8. Chaudhary MP, G Tupe S, V Deshpande M. Chitin synthase inhibitors as antifungal agents. Mini Rev Med Chem 2013;13:222-36.
9. Sheng C, Zhang W, Zhang M. Homology modeling of lanosterol 14 ?-demethylase of Candida albicans and Aspergillus fumigatus and insights into the enzyme-substrate interactions. J Biomol Struct Dyn 2004;22:91-9.
10. Guan Z, Chai X, Yu S. Synthesis, molecular docking, and biological evaluation of novel triazole derivatives as antifungal agents. Chem Biol Drug Des 2010;76:496-8.
11. Chai X, Zhang J, Cao Y. Design, synthesis and molecular docking studies of novel triazole as an antifungal agent. Eur J Med Chem 2011;46:3167-76.
12. Kelley LA, Mezulis S, Yates CM. The phyre2 web portal for protein modeling, prediction and analysis. Nature Protocols 2015;10:845-58.
13. Laskowski RA, MacArthur MW, Thornton JM. PROCHECK: validation of protein structure coordinates. International Tables of Crystallography, Vol. F. Crystallography of Biological Macromolecules. Kluwer Academic Publishers, The Netherlands; 2001. p. 722-5.
14. Kumar A, Bora U. Molecular docking studies of curcumin natural derivatives with DNA topoisomerase I and II-DNA complexes. Interdisciplinary Sci: Comput Life Sci 2014;6:285-91.
15. Morris GM, Goodsell DS, Halliday RS. Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998;19:1639-62.
16. Dupont S, Lemetais G, Ferreira T. Ergosterol biosynthesis: a fungal pathway for life on land? Evolution 2012;9:2961-8.
17. Maseet M, Khan N, Basir SF. Ergosterol biosynthesis and pathogenicity markers inhibition of candida albicans by fungus mediated silver nanoparticles. World J Pharm Pharm Sci 2016;2:600-18.
18. Prasad R, Shukla S, Singh A. Insights into candida lipids. In: Candida albicans: Cell Mol Biol; 2017. p. 417-28.
19. Chen SC, Sorrell TC. Antifungal agents. Med J Aust 2007;7:404.
20. Zhao J, Xu Y, Li C. Association of T916C (Y257H) mutation in candida albicans ERG11 with fluconazole resistance. Mycoses 2013;3:315-20.
21. Rajput SB, Karuppayil SM. Small molecules inhibit growth, viability and ergosterol biosynthesis in candida albicans. Springer Plus 2013;2:26-32.
22. Ahmad A, Khan A, Akhtar F. Fungicidal activity of thymol and carvacrol by disrupting ergosterol biosynthesis and membrane integrity against candida. Eur J Clin Microbiol 2011;30:41-50.
23. Prasanna G, Ujwal A, Diliprajudominic S. A new pipeline to discover antimycotics by inhibiting ergosterol and riboflavin synthesis: the inspirations of siddha medicine. Med Chem Res 2014;23:2651-8.
24. Brown GD, Denning DW, Gow NA. Hidden killers: human fungal infections. Sci Transl Med 2012;4:1-9.
25. Cowen LE, Sanglard D, Howard SJ. Mechanisms of antifungal drug resistance. Cold Spring Harb Perspect Med 2014;5:1-22.
26. Morio F, Loge C, Besse B. Screening for amino acid substitutions in the Candida albicans Erg11 protein of azole-susceptible and azole-resistant clinical isolates: new substitutions and a review of the literature. Diagn Microbiol Infect Dis 2010;66:373-84.
27. Morschhauser J. The development of fluconazole resistance in Candida albicans–an example of microevolution of a fungal pathogen. J Microbiol 2016;54:192-10.
28. Mane A, Vidhate P, Kusro C. Molecular mechanisms associated with fluconazole resistance in clinical Candida albicans isolates from India. Mycoses 2016;59:93-7.
29. Marichal P, Koymans L, Willemsens S. Contribution of mutations in the cytochrome P450 14?-demethylase (Erg11p, Cyp51p) to azole resistance in Candida albicans. J Microbiol 1999;145:2701-13.
30. White TC, Marr KA, Bowden RA. Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 1998;11:382-21.
31. Ruge E, Korting HC, Borelli C. Current state of three-dimensional characterization of antifungal targets and its use for molecular modelling in drug design. Int J Antimicrob Agents 2005;26:427-41.
Published
01-11-2020
How to Cite
JADHAV, A. K., KHAN, P. K., & KARUPPAYIL, S. M. (2020). PHYTOCHEMICALS AS POTENTIAL INHIBITORS OF LANOSTEROL 14 Α-DEMETHYLASE (CYP51) ENZYME: AN IN SILICO STUDY ON SIXTY MOLECULES. International Journal of Applied Pharmaceutics, 12(4), 18–30. https://doi.org/10.22159/ijap.2020.v12s4.40100
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