Abstract
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.
Highlights
IntroductionCryptococcosis remains a significant cause of morbidity and mortality in immunocompromised people especially in sub-Saharan Africa [1]
Among fungal diseases, cryptococcosis remains a significant cause of morbidity and mortality in immunocompromised people especially in sub-Saharan Africa [1]
In the case of cryptococcosis, a life-threatening fungal disease in immunocompromised patients, studies indicated that cryptococcal species are developing resistance to the currently used azole drug fluconazole
Summary
Cryptococcosis remains a significant cause of morbidity and mortality in immunocompromised people especially in sub-Saharan Africa [1]. Cryptococcal species such as Cryptococcus neoformans and C. gatti are primarily responsible for this disease [2]. Treatment options for cryptococcosis are limited to only three drugs B, flucytosine, and fluconazole), with few compounds reaching clinical trials [3]. The treatment involves use of an azole drug, fluconazole, as primary or consolidation and maintenance therapy, followed by induction therapy with intravenous amphotericin B with or without flucytosine [4].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
