Abstract
In recent years, the increased frequency of drug-resistant strains of Cryptococcus neoformans has depleted our antifungal armory. In the present study, we investigated the inhibitory potential of ellagic acid (EA) against C. neoformans laccase through in silico and in vitro studies. For the first time, a homology modelling was estab-lished to model laccase and modelled protein served as a receptor for docking EA. Thermodynamic stability of the docked complex was ascertained by molecular dynamics simulation (MD). The analysis of root mean square deviation and fluctuation of alpha carbons of protein justifies the stability of the bound EA in the binding pocket of laccase. Frontier molecular orbitals of the EA was studied by density functional theory-based optimization by using the Lee-Yang-Parr correlation functional (B3LYP) approach. Negative values of the highest occupied/un-occupied molecular orbitals (HOMO/LUMO) indicated that laccase with EA forms a stable complex. Interest-ingly, EA inhibited laccase activity both in vitro and in yeast cells of C. neoformans. Moreover, EA treatment remarkably inhibited the proliferation of C. neoformans inside macrophages. The findings of the present study unveil the molecular basis of the interactions of laccase with EA, which may prove to be beneficial for designing laccase inhibitors as potential anti-cryptococcal agents.