Identification of novel inhibitors against Med15a KIX domain of Candida glabrata

Candida glabrata, the second most common cause of invasive fungal infections, exhibits multi-drug resistance to commonly used antifungal drugs. To counter this resistance, there is a critical need for novel antifungals. This study identifies small molecule inhibitors that target a three-helix bundle...

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Bibliographic Details
Published in:International journal of biological macromolecules 2023-12, Vol.253, p.126720-126720, Article 126720
Main Authors: Waseem, Mohd, Das, Shubhashis, Mondal, Debarati, Jain, Monika, Thakur, Jitendra K., Subbarao, Naidu
Format: Article
Language:English
Subjects:
antifungal agents
Candida glabrata
Chebulinic acid
data collection
domain
fungi
Med15a KIX domain
Molecular dynamic simulation
molecular dynamics
multiple drug resistance
phytochemicals
transcription factors
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Summary:Candida glabrata, the second most common cause of invasive fungal infections, exhibits multi-drug resistance to commonly used antifungal drugs. To counter this resistance, there is a critical need for novel antifungals. This study identifies small molecule inhibitors that target a three-helix bundle KIX domain in the Med15a Mediator subunit of Candida glabrata (CgMed15a KIX). This domain plays a crucial role by interacting with the Pleiotropic Drug Resistance transcription factor Pdr1, a key regulator of the multidrug resistance pathway in Candida glabrata. We performed high throughput computational screening of large chemical datasets against the binding sites of the CgMed15a KIX domain to identify novel inhibitors. We selected six potential candidates with high affinity and confirmed their binding with the CgMed15a KIX domain. A phytochemical compound, Chebulinic acid binds to the CgMed15a KIX domain with a KD value of 0.339 μM and shows significant inhibitory effects on the growth of Candida glabrata. Molecular dynamics simulation studies further revealed the structural stability of the CgMed15a KIX-Chebulinic acid complex. Thus, in conclusion, this study highlights Chebulinic acid as a novel potential antifungal compound against Candida glabrata.
ISSN:0141-8130
1879-0003
DOI:10.1016/j.ijbiomac.2023.126720