Computational and Experimental Identification of Low-Toxicity Antifungal Compounds for Cryptococcal Meningitis and Candidiasis

Abstract

Cryptococcal meningitis and candidiasis are life-threatening fungal infections predominantly affecting immunocompromised populations, such as those living with HIV/AIDS. Current antifungal treatments are limited by high toxicity, increasing resistance, and accessibility challenges in low-resource settings. This study aimed to identify novel, low-toxicity antifungal compounds using computational drug discovery tools and to validate their antifungal potential in vitro. Fluconazole and flucytosine analogues were screened using SwissSimilarity, ZINC Pharmer, SwissADME, and ProTox 3.0 to assess structural similarity, pharmacokinetics, and toxicity. The most promising compounds, ZINC79355076 and ZINC000035660397, were evaluated using molecular docking and in vitro agar dilution methods against Cryptococcus neoformans and Candida albicans. ZINC79355076 demonstrated a superior docking score (-9.7), favorable pharmacokinetics, and lower predicted toxicity compared to fluconazole (-7.5). Similarly, ZINC000035660397 exhibited enhanced binding affinity (-8.1) and a higher LD50 compared to flucytosine. In vitro assays confirmed that both analogues inhibited fungal growth comparably or more effectively than current standard treatments. ZINC79355076 and ZINC000035660397 analogs are promising drugs for the treatment of cryptococcal meningitis and candidiasis with improved pharmacological profiles and reduced toxicity. Additional in vivo experimentation and clinical trials are recommended to elucidate their therapeutic potential, particularly in resource-limited settings.