感冒229E病毒3CL蛋白酶抑制剂金丝桃苷衍生物的合成及其构效关系研究

目的寻找作为感冒229E抗原型冠状病毒3CL蛋白酶抑制剂的新化学结构。方法运用分子对接方法在ACD化合物库中发现天然产物金丝桃苷是潜在的新型抑制剂,借助分子模拟的方法进行结构改造,设计并合成了5个金丝桃苷衍生物,采用表面等离子共振(SPR)法测试这些化合物与该蛋白酶的结合能力。结果与结论衍生物Ⅱ、Ⅲ、Ⅳ与蛋白酶的结合能力比原天然产物Ⅰ提高了3倍以上,它们的结合构象也明显不同于Ⅰ与SARS病毒3CL蛋白酶的结合构象。这些结合模式的差异为设计选择性更好的感冒病毒3CL蛋白酶抑制剂提供了有益的参考信息。将计算机辅助药物分子设计、有机合成和生物活性测试有机地结合起来,是发现和设计感冒229E型病毒3CL蛋白酶新型选择性抑制剂的有效途径。

Synthesis and SAR studies on hyperin and its analogues as 3CL protease inhibitors of human coronavirus 229E

Aim To discover new chemical structures as 3CL protease inhibitors of human coronavirus 229E(HCoV-229E).Methods A natural product,hyperin,was discovered as a potential inhibitor of the HCoV-229E 3CL protease by molecular docking.Five new analogues were then designed based on the receptor-ligand interaction mechanism,and successfully synthesized,followed by a bioassay study with surface plasmon resonance technique.Results and conclusion Three new analogues were found to be more active than hyperin.The binding conformations of the newly designed compounds to HCoV-229E 3CL protease are different from that to SARS 3CL protease.Thus,highly specific inhibitors of HCoV-229E 3CL protease could be designed based on the difference.It would be an efficient approach to discover and design highly active and specific inhibitors of 3CL protease of human coronavirus 229E as potential drug leads against human cold coronavirus 229E by integrating virtual screening,molecular modeling and design,organic synthesis with bioassay.