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Article

In Silico Structural Modeling and Analysis of Interactions of Tremellomycetes Cytochrome P450 Monooxygenases CYP51s with Substrates and Azoles

1
Department of Biochemistry and Microbiology, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa 3886, South Africa
2
College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Stefana Banacha 2C, 02-097 Warsaw, Poland
3
Biological and Chemical Research Center, Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
4
Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
*
Authors to whom correspondence should be addressed.
Authors contributed equally to the work.
Academic Editor: Patrick M. Dansette
Int. J. Mol. Sci. 2021, 22(15), 7811; https://doi.org/10.3390/ijms22157811
Received: 25 February 2021 / Revised: 21 May 2021 / Accepted: 25 May 2021 / Published: 22 July 2021
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 3.0)
Cytochrome P450 monooxygenase CYP51 (sterol 14α-demethylase) is a well-known target of the azole drug fluconazole for treating cryptococcosis, a life-threatening fungal infection in immune-compromised patients in poor countries. Studies indicate that mutations in CYP51 confer fluconazole resistance on cryptococcal species. Despite the importance of CYP51 in these species, few studies on the structural analysis of CYP51 and its interactions with different azole drugs have been reported. We therefore performed in silico structural analysis of 11 CYP51s from cryptococcal species and other Tremellomycetes. Interactions of 11 CYP51s with nine ligands (three substrates and six azoles) performed by Rosetta docking using 10,000 combinations for each of the CYP51-ligand complex (11 CYP51s × 9 ligands = 99 complexes) and hierarchical agglomerative clustering were used for selecting the complexes. A web application for visualization of CYP51s’ interactions with ligands was developed (http://bioshell.pl/azoledocking/). The study results indicated that Tremellomycetes CYP51s have a high preference for itraconazole, corroborating the in vitro effectiveness of itraconazole compared to fluconazole. Amino acids interacting with different ligands were found to be conserved across CYP51s, indicating that the procedure employed in this study is accurate and can be automated for studying P450-ligand interactions to cater for the growing number of P450s. View Full-Text
Keywords: cytochrome P450 monooxygenases; CYP51; Tremellomycetes; sterol 14α-demethylase; Cryptococcus neoformans; drug-resistance; web-application; docking cytochrome P450 monooxygenases; CYP51; Tremellomycetes; sterol 14α-demethylase; Cryptococcus neoformans; drug-resistance; web-application; docking
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MDPI and ACS Style

Akapo, O.O.; Macnar, J.M.; Kryś, J.D.; Syed, P.R.; Syed, K.; Gront, D. In Silico Structural Modeling and Analysis of Interactions of Tremellomycetes Cytochrome P450 Monooxygenases CYP51s with Substrates and Azoles. Int. J. Mol. Sci. 2021, 22, 7811. https://doi.org/10.3390/ijms22157811

AMA Style

Akapo OO, Macnar JM, Kryś JD, Syed PR, Syed K, Gront D. In Silico Structural Modeling and Analysis of Interactions of Tremellomycetes Cytochrome P450 Monooxygenases CYP51s with Substrates and Azoles. International Journal of Molecular Sciences. 2021; 22(15):7811. https://doi.org/10.3390/ijms22157811

Chicago/Turabian Style

Akapo, Olufunmilayo O., Joanna M. Macnar, Justyna D. Kryś, Puleng R. Syed, Khajamohiddin Syed, and Dominik Gront. 2021. "In Silico Structural Modeling and Analysis of Interactions of Tremellomycetes Cytochrome P450 Monooxygenases CYP51s with Substrates and Azoles" International Journal of Molecular Sciences 22, no. 15: 7811. https://doi.org/10.3390/ijms22157811

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