In silico approach to identify the potential targets of Alexidine dihydrochloride and Hexachlorophene in human fungal pathogen C. glabrata

Abstract

Widespread usage of antifungals has led to the development of antifungal resistance, causing a change in the epidemiology of the responsible agents from albicans to non-Candida albicans species. Pharmaceutical repurposing is an alternate strategy that has provided a cost-effective method to address the increasing resistance to antifungal medications. The objective of this work was to examine the antifungal properties of Alexidine dihydrochloride (AXD) and Hexachlorophene (HCP) against a non-Albicans Candida model, C. glabrata. The lowest inhibitory doses of AXD and HCP against C. glabrata were determined by in vitro methods to be 0.69-1.03 µM and 14.75-19.66 µM, respectively. The minimum doses of AXD and HCP that caused fungicidal effects were defined as 1.375 µM and 61.44 µM, respectively. Three proteins involved in crucial physiological pathways, namely cell wall production (Kre1p, Kre2p, Ecm33p), membrane calcium channel (Mid1p, Ecm7p), and ergosterol biosynthesis (Erg5p), were chosen as potential targets for the medications due to their functions in survival and disease development. SWISS MODEL was used to create the 3D structures of predicted targets of C. glabrata. The quality of these structures was assessed using Ramachandran plot statistics. AXD and HCP were analyzed by docking software AutoDock Vina against these targets. The findings of computational investigations have shown that both medicines exhibit interaction affinities with all the selected protein types. The binding energy profiles of AXD and HCP showed that Mid1p had the lowest binding energies at -10.1 kcal/mol and -9.2 kcal/mol, respectively. Kre2p had binding energies of -7.9 kcal/mol and -7.1 kcal/mol, respectively. Erg5p had binding energies of -6.6 kcal/mol and -6.2 kcal/mol, respectively. Ecm7p had binding energies of -6.6 kcal/mol and -6.1 kcal/mol, respectively. Recm7p had binding energies of -4.8 kcal/mol and -7.7 kcal/mol, respectively. These results suggest that these genes are likely targets of the two drugs in C. glabrata.

Keywords

• Drug targets
• Drug repurposing
• Homology modelling
• In silico docking
• Non-albicans Candida