応用生物情報学および計算生物学ジャーナル

ADME/T Prediction, Molecular Docking, and Biological Screening of 1,2,4-Triazoles as Potential Antifungal Agents

Usman Rasheed, Umair Ilyas, Shahiq Uz Zaman, Syed Aun Muhammad, Hasan Afzaal and Reem Altaf

Clinical needs for new antifungal agents have gradually and steadily increased with the rise of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections.Triazoles are taken as potential antifungal molecules considering the existing portfolio of antifungal agents available in the market. This study was aimed to evaluate antifungal potential of 4-Amino 5-(2-Hydroxyphenyl)-1,2,4-Triazole-3-Thione and4-(2-hydroxybenzalidine)amine-5-(2-hydroxy)phenyl-1,2,4-triazole-3-thiol using molecular docking and in-vitro antifungal screening approach. This study was further designed to evaluate potential drug likeness properties and ADME/T prediction of aforementioned experimental triazoles. 3D crystal model of cytochrome P450 lanosterol 14 α-demethylaseenzyme was acquired from Protein Data Bank (PDB ID 5EQB). Docking studies revealed that both experimental compounds showed stable binding complex with lowest binding affinity values compared to reference standard Fluconazole (-6.8, -7.8 and -7.1Kcal/mol respectively for UI, UIA and Fluconazole) against cytochrome P450 lanosterol 14 α-demethylase, which is a key yeast target.In-vitro evaluation revealed that both experimental triazoles especially UIA showed promising MIC values, 24, 48 and 80 μg against Candida albican, Candida tropicalis and Candida glabrata respectively. Rat acute toxicity prediction using GUSAR model suggested that both experimental molecules were virtually non toxic when computationally studied through IV, IP, SC and oral routes of administration. This experimental work concludes that both triazoles possess strong fungicidal potential and should be further explored. In-silico work in current study further proposes an exceptional strategy for drug discovery with minimum cost and time