Betulinic acid and Drummondin E: Potential inhibitors of Unfolded Protein Response Pathway of Candida auris

Abstract

Candida auris is a rapidly emerging global public health concern. The increasing mortality in immunocompromised patients is mostly attributed to the rise of drug-resistant clinical isolates. Low bioavailability and toxicity of the existing antifungals further exacerbate the condition. Unfolded protein response (UPR) has been linked to fungal pathogenesis in previous studies. In this study the two hallmark proteins of the UPR pathway, Hac1p and Ire1p, were targeted to identify novel antifungals. Different phytochemicals showing various therapeutic potential were selected. Using various bioinformatics tools, the molecular property, bioactivity, toxicity, drug-likeness of these compounds were determined. The compounds showing the best properties were analyzed for their ability to interact with UPR proteins by molecular docking study. Finally, the molecular dynamics simulation analysis was performed to determine the stability of the interactions between the phytochemicals and the target protein. Flinderole-B, Drummondin-E, Betulinic acid, Ursolic acid, Oleanolic acid, Stigmasterol showed good drug-likeness scores. They were also found to be non-carcinogenic, and non-toxic; and followed Lipinski’s rule of five. Based on the simulation analysis Betulinic acid showed the best potential to target Hac1p while Drummondin-E showed the best potential to target Ire1p. Betulinic acid and Drummondin E could be potential inhibitors of the UPR pathway in C. auris. However, further in vitro and in vivo studies are needed to corroborate their antifungal potential.