Construction and Evaluation of Molecular Models: Guide and Design of Novel SE Inhibitors

Squalene epoxidase (SE) was considered an important antifungal target to block ergosterol synthesis. In this study, molecular models of CASE including the homology model and the SBP were constructed, respectively. Three representative SE inhibitors were selected and docked into the active site of CASE. Subsequently, the novel SE inhibitors were designed based on the analysis of the inhibitor binding mode and the distribution of pharmacophore features. These compounds were further synthesized and tested in vitro. They exhibited a certain degree of antifungal activity, especially compound 7a-2, which also has a significant inhibitory effect on resistant fungi. Further analysis found that compound 7a-2 could inhibit SE, which is similar to naftifine. The study proved the rationality of the molecular models; they can help us design and discover more potent antifungal SE inhibitors.