基于分子对接预测靶点ACE2和IL-6R研究归芪白术方治疗新型冠状病毒肺炎的物质基础及其作用机制

Material basis and action mechanism of Guiqi Baizhu Fang( 归芪白术方) in the treatment of COVID-19 based on molecular docking prediction for target ACE2 and IL-6R

目的基于计算机辅助药物设计(CADD),从阻断血管紧张素转换酶II(ACE2,新型冠状病毒受体)及白细胞介素-6受体(IL-6R,细胞炎症因子风暴关键受体)2个方面探索具有益气健脾、祛湿化瘀功效的归芪白术方"排毒""抑制炎症风暴"作用的物质基础和分子机制。方法使用化学信息学方法构建归芪白术方药物小分子化合物库,选择ACE2和IL-6R蛋白作为研究靶蛋白,确定靶蛋白晶体结构及活性位点,在此基础上通过分子对接,筛选能够与靶蛋白有效结合的药物小分子化合物。结果归芪白术方中有483个小分子化合物符合类药五原则,其中有224个小分子化合物与ACE2靶蛋白对接得分绝对值≥4分,有225个小分子化合物与IL-6R靶蛋白对接得分绝对值≥4分;归芪白术方小分子化合物MOL002298(Aloeemodin)、MOL004858(Gancaonin C)等与靶蛋白对接得分绝对值较高,MOL000040(Scopoletin)、MOL000098(Quercetin)等可同时与2个靶蛋白结合。结论归芪白术方含有多种有效成分,既含有可阻断新型冠状病毒受体ACE2的小分子化合物,也含有可靶向阻断细胞炎症因子风暴受体IL-6R的小分子化合物,可通过多点显效、协同增效而发挥扶正祛邪的作用。

Objective To explore the material basis and action mechanism of"detoxification"and"inhibiting inflammatory storm"in Guiqi Baizhu Fang( 归芪白术方,GBF) with the efficiency of replenishing qi to invigorate spleen and expelling dampness and resolving stagnation from the 2 aspects of blocking angiotensin-converting enzyme2( ACE2,novel coronavirus receptor) and interleukin-6 receptor( IL-6 R,inflammatory cytokines storm key receptor),based on computer-aided design and drafting( CADD). Methods The small molecule compound library of GBF was constructed by chem-informatics method. ACE2 and IL-6 R protein were selected as the research target protein. On the basis of determination of crystal structure and active site of target protein,the small molecule compound that can effectively bind to the target protein was screened by molecular docking. Results There are 483 small molecule compounds conformed to the five principles of drug-likeness in GBF,of which 224 small molecule compounds have absolute value of a docking score of ≥ 4 with ACE2 target protein,225 small molecule compounds have absolute value of a docking score of ≥4 with IL-6 R target protein. MOL002298( Aloeemodin),MOL004858( Gancaonin C) and other small molecular compounds of GBF have higher absolute value of docking scores with the target protein. MOL000040( Scopoletin),MOL000098( Quercetin) and other small molecular compounds can bind to two target proteins at the same time. Conclusion There are many effective ingredients in GBF,including small molecular compounds not only can block ACE2 but also can block IL-6 R,which can play a role of strengthening healthy qi and removing pathogenic factors through multi-point effect and synergistic synergy.