Issue 45, 2019

Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors

Abstract

Fungal infections and drug-resistance are rapidly increasing with the deterioration of the external environment. Squalene cyclooxygenase (SE) and 14α-demethylase (CYP51) are considered to be important antifungal targets, and the corresponding pharmacophore models can be used to design and guide the discovery of novel inhibitors. Therefore, the common feature pharmacophore model (SE inhibitor) and structure-based pharmacophore model (CYP51 receptor) were constructed using different methods in this study. Then, appropriate organic fragments were selected and superimposed onto the pharmacophore features, and compounds 5, 6 and 8 were designed and produced by linking these organic fragments. It is noteworthy that compound 8 can simultaneously match the features of both the SE and CYP51 pharmacophores. Further analysis found that these compounds exhibit a potent antifungal activity. Preliminary mechanistic studies revealed that compound 8 could undergo dual-target inhibition (SE and CYP51) of Candida albicans. This study proved the rationale of pharmacophore models (SE and CYP51), which can guide the design and discovery of new antifungal inhibitors.

Graphical abstract: Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors

Associated articles

Supplementary files

Article information

Article type
Paper
Submitted
16 May 2019
Accepted
22 Jul 2019
First published
22 Aug 2019
This article is Open Access
Creative Commons BY license

RSC Adv., 2019,9, 26302-26314

Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors

Y. Dong, M. Liu, J. Wang, Z. Ding and B. Sun, RSC Adv., 2019, 9, 26302 DOI: 10.1039/C9RA03713F

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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