随着真菌耐药性问题的日益严重，抗真菌药物研发又重新成为创新药物研究的热点领域。麦角甾醇是真菌细胞膜的重要组成部分，角鲨烯环氧化酶（SE）和14α-去甲基酶（CYP51）是催化麦角甾醇生物合成的关键酶，也是重要的药物靶标。我们希望通过开发以角鲨烯环氧化酶和14α-去甲基酶为双靶点的新型抗真菌抑制剂来解决真菌耐药性问题。本项目拟综合运用药效团模型和以受体为基础的双靶点联合筛选策略进行高通量虚拟筛选，同时结合抗真菌活性实验测定，发现先导化合物；在此基础上进行多轮结构优化、改造以及合成衍生物，以期最终发现安全有效、具有开发前景的双靶点抗真菌目标化合物。本课题的顺利展开，在为发现新一代抗真菌抑制剂打下基础的同时，还将为解决真菌耐药性问题提供方向。

As the problem of fungal resistance becomes increasingly serious, the research of antifungal drug again becomes the focus of innovative drug research field. Ergosterol is an important part of fungal cell membranes, squalene epoxidase (SE) and 14α-demethylase (CYP51) as important drug targets are the key enzymes in ergosterol biosynthesis. We hope to find the novel antifungal inhibitors of squalene epoxidase and 14α-demethylase as bi-target and solve the problem of fungal resistance. In the project, the high-throughput virtual screening will be carried out using the pharmacophore model and the receptor-based bi-target screening strategy, the lead compound will be found in combining with the antifungal activity test. On this basis, the studies will be focused on optimization, modification of the lead compound and synthetic derivatives, the aim is to eventually find the safe and effective bi-target of antifungal compounds with promising prospect. The success of this project will provide a theoretical basis for the rational design of the new generation antifungal compounds and a direction to solve the problem of fungi resistance.