Sari, S, Kart, D, Sabuncuoğlu, S, Doğan, İS, Özdemir, Z, Bozbey, İ, Gencel, M, Eşsiz, Ş, Reynisson, J ORCID: https://orcid.org/0000-0003-4174-9512, Karakurt, A, Saraç, S and Dalkara, S (2019) Antifungal screening and in silico mechanistic studies of an in-house azole library. Chemical Biology & Drug Design.

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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.

Item Type: Article
Additional Information: This is the pre-peer reviewed version of the following article: Sari, S, Kart, D, Sabuncuoğlu, S, Doğan, İS, Özdemir, Z, Bozbey, İ, Gencel, M, Eşsiz, Ş, Reynisson, J , Karakurt, A, Saraç, S and Dalkara, S (2019) Antifungal screening and in silico mechanistic studies of an in-house azole library. Chemical Biology & Drug Design, which has been published in final form at http://doi.org/10.1111/cbdd.13587. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Uncontrolled Keywords: Biological Screening, Molecular Modeling, Structure-Based Drug Design
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy
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Depositing User: Symplectic
Date Deposited: 10 Jul 2019 10:37
Last Modified: 10 Jul 2019 10:40
URI: http://eprints.keele.ac.uk/id/eprint/6572

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