Chemoinformatics exploration of synthetically accessible N-heterocycles: uncovering new antifungal lead candidates

Abstract

Fungal infections caused by Candida albicans pose a significant global health challenge due to their high morbidity, mortality, and the growing prevalence of drug resistance. The failure of existing antifungal agents against resistant strains underscores the urgent need for novel therapeutic alternatives. In response to this challenge, we have created an in-house library of biologically relevant nitrogenous heterocycles to screen against the resistant C. albicans dihydrofolate reductase (DHFR), with the aim of identifying potential antifungal leads. Using computational tools such as molecular docking and dynamics simulations, we identified two promising leads based on isoquinoline scaffold. The stability of these leads was further assessed using quantum chemical descriptor calculations. Screening results indicate that these isoquinoline-based compounds could serve as potential antifungal candidates, offering a foundation for the development of new therapies to combat resistant C. albicans infections. Further experimental studies, including animal model testing, are necessary to validate and confirm our findings.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00359-9.

Keywords: Candida; DFT studies; Dihydrofolate reductase; Docking; Dynamics simulation; N-heterocycles.