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

• DOI: 10.1111/cbdd.13587
• Publication Date: 2019-07-01T15:49:16Z
• Authors: Suat Sari; Didem Kart; Suna Sabuncuoğlu; İnci Selin Doğan; Zeynep Özdemir; İrem Bozbey; Melis Gencel; Şebnem Eşsiz; Jóhannes Reynisson; Arzu Karakurt; Selma Saraç; Sevim Dalkara
• Keywords: Azoles; Models, Molecular; 0301 basic medicine; Antifungal Agents; Cell Survival; Drug Evaluation, Preclinical; Molecular modeling; RS; Cell Line; Fungal Proteins; Small Molecule Libraries; Mice; 03 medical and health sciences; Catalytic Domain; Animals; Humans; Computer Simulation; Candida; 0303 health sciences; Molecular Structure; Candidiasis; Fibroblasts; 3. Good health; 14-alpha Demethylase Inhibitors; Cytochrome P450 Family 51; Biological screening; Structure-based drug design; Protein Binding

AbstractSystemic 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 modeling 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 simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.