基于植物成分的蛋白酶激活受体1拮抗剂的虚拟筛选和实验筛选

目的 基于植物成分寻找具有蛋白酶激活受体1（PAR-1）拮抗作用的新结构类别。方法 将30个中药成分与PAR-1进行分子对接计算，通过评价对接得分、占据空间、氢键等指标进行虚拟筛选。采用体外豚鼠血小板聚集实验进行活性的实验筛选。结果 虚拟筛选提示隐丹参酮（T30）和葛根素肉桂酰酯（T21）具有PAR-1拮抗作用的前景。实验筛选表明T21、杨梅素（T5）、大黄素（T28）、麦角甾苷（T29）具有明确的作用。通过深入分析虚拟和实验筛选结果表明，残基258和空腔III对活性的影响是决定性的，其他各区在活性调节中，II区主要是氢键和匹配的要求，IV和V区主要是疏水性匹配性，氢键结合对于进一步提升活性具有重要意义。结论 基于阳性药的结合模式的发现了T21，结合理论和实验还发现T5、T28、T29属于一种新的作用模式，为寻找PAR-1拮抗剂的结构类别提供了新的方向。

Virtual and experimental screening of protease activated receptor 1 antagonist in plant ingredients

Objective To find the new type of structures with protease activated receptor 1 (PAR-1) inhibition from plant ingredients. Methods Thirty ingredients were docked into PAR-1, and then, docking score, occupied space, hydrogen bonding, and other indicators were used for virtual screening. In vitro platelet aggregation experiments in guinea pig were performed to screen the activities of all ingredients. Results Virtual screening suggested that T30 and T21 had the prospects to inhibit PAR-1. Experiment screening showed that T21, T5, T28, and T29 have the real inhibitory effects on PAR-1. Combination analyses of virtual and experimental screening suggested the following results. Residue 258 and area III had the key effects. Hydrogen matching was required at area II. Area IV and V regions mainly need hydrophobic match. The hydrogen bonding played an important role in improving the activity. Conclusion According to the binding mode of control drug, T21 is found. To examine the binding mode of T5, T28, and T29, their experimental activities suggest a novel action mode which provides a new direction to find the PAR-1 antagonist.