Targeting the deSUMOylase Ulp2 in Candida glabrata for antifungal therapies: in silico identification of silymarin and honokiol as potential inhibitors.

Fungal infections, especially those caused by naturally drug-resistant strains such as Candida glabrata, present a significant global health concern due to the limitations of existing antifungal treatments, which are often compromised by toxicity and resistance. In this study, we investigate the potential SUMO-specific protease, Ulp2, in C. glabrata (CgUlp2), a deSUMOylating enzyme essential for maintaining protein homeostasis, as a target for antifungals. Structural analyses revealed significant differences between CgUlp2 and its human counterpart. Molecular docking studies identified a potential binding region between CgUlp2 and CgSmt3, which led us to screen for small molecules that could interfere with this protein–protein interaction. We identified the FDA-approved compounds silymarin and honokiol as promising candidates through pharmacophore-based virtual screening. Docking results revealed that silymarin and honokiol interact with the CgUlp2–CgSmt3 protein complex. Consistent with these computational findings, our growth assays show that silymarin and honokiol inhibit the growth of C. glabrata, and overexpression of CgUlp2 could partially rescue this growth defect. These findings underscore the potential of CgUlp2 as a key target for developing new antifungals, representing a significant step forward in the fight against fungal infections. While this study offers promising computational insights, it is limited to in silico predictions. Experimental validation, including enzyme inhibition assays and in vivo efficacy testing, is essential for clinical translation.