氮唑类药物是抗深部真菌感染的主力和研究热点，面临耐药、抗菌谱窄、深部真菌感染致死率高（约50%）等问题，近十年来发展缓慢，关键是其侧链结构创新乏力，迫切需要基于准确的靶酶与药物侧链结合模式的药物设计方法。我们前期运用不对称合成新路线获得优效广谱、结构新颖的手性化合物NT-2。本课题拟采用2015年报道的首个致病真菌CYP51晶体结构，运用SYBAL软件，开展多轮次“设计-对接-合成-测活-优化设计”循环，合成并测活200个NT-2类似物，研究“结构-活性-对接打分”三者关系，获得高可信度的CYP51与药物结合模式。随后，选取高活性化合物，将光亲和基团引入其侧链，设计合成筛选活性小分子探针，捕获其侧链部分与CYP51的结合位点和序列，验证并修正虚拟对接模式，优化药物设计方法，再设计合成100个化合物并测活，目标获得2-3个对白念珠菌、烟曲霉菌和新生隐球菌的药效均优于NT-2的新化合物。

Azole antifungals are the first-line drugs in treating invasive fungal infections, and keep being hotpoint in antifungal study. Facing the problems including resistance, antifungal spectrum to be widen, and high motality of invasive fungal infections (about 50%), azole antifungal has been developed slowly in the past decade due to the lack of innovation in optimizing the side chain in their structures, thus it urgently need new drug design method based on true mode of azole antifungal, especially the side chain of it, binding its target. We previously found a novel antifungal compound NT-2, which exhibits higher efficacy and wider antigunngal spectrum than voriconazole and fluconazole. NT-2 was prepared by novel asymmetric synthesis. In this project, we plan to optimize NT-2, and initially prepare and screen 200 derivatives. Based on the CYP51 crystal of Aspergillus funigatus reported in 2015, we will set up a new method for virtue screening with SYBAL software, then run several rounds of “design-virtue screening-synthesis-screening- method optimization and design”. By investigating the relationships of “structure-activity-virtue docking score”, we are expecting to obtain further insight of the binding mode of CYP51 with the side chain in azoles. Next, we plan to introduce photoaffinity group into the side chain of the active compounds to prepare photoaffinity small-molecule probes which can capture their binding sites and peptide sequences in CYP51, thus can validate the virtue docking and optimize our drug design method. Another 100 compounds, designed by new method, will be prepared and screened. This project is aimed to find out 2-3 novel antifungal compounds with more potential than NT-2 against Candida albicans, Crytococcus Neofonmans and Aspergillus funigatus.