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Antifungal screening and in silico mechanistic studies of an in-house azole library

Reynisson

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Abstract

Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis, however non-albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first-choice antifungal drugs for candidiasis, however they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in-house azole library of 65 compounds to identify hit matter followed by a molecular modelling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics (MD) simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 was stable demonstrating excellent binding. This article is protected by copyright. All rights reserved.

Acceptance Date Jul 1, 2019
Publication Date Jul 1, 2019
Publicly Available Date Mar 28, 2024
Journal Chemical Biology & Drug Design
Print ISSN 1747-0277
Publisher Wiley
DOI https://doi.org/10.1111/cbdd.13587
Keywords Biological Screening, Molecular Modeling, Structure-Based Drug Design
Publisher URL http://doi.org/10.1111/cbdd.13587

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