Sulfonylurea类ALS/AHAS抑制剂作用方式的分子对接研究和新抑制剂的虚拟筛选

Docking Study on the Binding Modes of Sulfonylurea Analogues to ALS/AHAS and Virtual Screen of Novel Inhibitors

采用Dock5和Autodock3的组合,从乙酰乳酸合成酶(ALS)的晶体结构出发,对五个磺酰脲分子和三个类磺酰脲分子与ALS的相互作用方式进行了详细的分子对接研究,并结合对ALS与氯嘧磺隆(类磺酰脲)共结晶的复合物晶体结构的分析得出了一个简化的药效团模型,与前人利用其它手段得到的药效团模型一致.结合此药效团模型并根据sulfonylurea类分子与ALS的作用机理,我们对425个具有不同除草和杀虫作用的已知农药和ALS进行了分子对接研究和筛选,从中发现了一些可能对ALS有抑制作用的农药分子.此结果可以很好地解释这类农药的结构和活性的关系,对设计、开发新ALS抑制剂的先导化合物提供依据和指导.

From the crystal structure of acetolactate synthase （ALS） or acetohydroxyacid synthase （AHAS）, a docking study was performed to explore the binding modes of 8 sulfonylurea analogues to ALS as its inhibitors using combined DOCK5 and Autodock3 programs. On the basis of the modes and the crystal structure of ALS and sulfonylurea complex, a simplified pharmacophore was obtained. Accordingly, 425 known pesticides, which were not previously found to have the function of inhibiting ALS, were screened by the same docking methods. A number of molecules were found to have the function of inhibition to ALS. It was predicted that those molecules could be used as the inhibitor of ALS. This result revealed the structure-activity relationships of this＇kind of pesticide and can be used to design and synthesize novel lead compound as ALS inhibitors.