IN SILICO SCREENING OF NATURAL ERGOSTEROL PATHWAY INHIBITORS IN CANDIDA ALBICANS
TL;DR
The findings support the potential of these flavonoids as selective, low-toxicity SQLE inhibitor candidates and reinforce the value of in silico screening in guiding future in vitro and in vivo validation of novel antifungal therapies derived from plant biodiversity.
Abstract
Fungal infections pose a growing global health threat, worsened by rising antifungal resistance and a limited therapeutic arsenal. Squalene epoxidase (SQLE), an enzyme essential for ergosterol biosynthesis, is a validated antifungal target exploited by drugs such as allylamines and benzylamines. This study aimed to perform an in silico prospection of natural antifungal compounds through molecular docking to identify potential SQLE inhibitors of Candida albicans among thirteen selected phytocompounds, compared against five reference antifungals (terbinafine, naphthifine, butenafine, tolciclate, and liranaftate). The SQLE structure (UniProt Q92206) was obtained via AlphaFold prediction, and its binding pockets were identified using PrankWeb, followed by molecular docking and intermolecular interaction analysis with BIOVIA Discovery Studio; toxicity was predicted using ProTox 3.0 and STopTox. Isorhamnetin, baicalin, apigenin-7-O-glucoside, and silibinin showed the most promising binding affinities, converging on key active-site residues (ASP332, VAL45, PRO339) shared with reference antifungals, while displaying a distinct interaction profile dominated by hydrogen bonding rather than hydrophobic contacts. These phytocompounds also showed favorable predicted toxicity profiles, with low acute toxicity and no organ-specific toxicity alerts. The findings support the potential of these flavonoids as selective, low-toxicity SQLE inhibitor candidates and reinforce the value of in silico screening in guiding future in vitro and in vivo validation of novel antifungal therapies derived from plant biodiversity.