胆汁淤积是临床常见疾病之一，目前治疗胆汁淤积的西药非常缺乏，而中药如茵栀黄方疗效显著。课题组在国家自然科学基金项目（81373927）的研究中发现，茵栀黄方中活性成分京尼平苷可同时激活核受体CAR和FXR，从而调控下游靶基因发挥“利胆退黄”作用，但京尼平苷的代谢物具有一定的肝毒性。如何利用京尼平苷的结构优势同时避免其代谢物毒性发现新的“CAR+FXR”双重激动剂成为本项目的主要研究内容。项目拟在明确京尼平苷与CAR和FXR相互作用模式的基础上，采用“in silico→in vitro→in vivo”层层递进筛选评价策略，通过基于分子对接方法的虚拟筛选，依次在细胞和动物水平上对药效和毒性进行系统评价，以期获得具有“CAR+FXR”双重激动作用的“利胆退黄”双重功效的天然活性化合物。通过本项目的实施，有望发现新型治疗胆汁淤积的先导化合物，同时也为从中药中发现多靶点治疗药物提供一种研究思路。

Cholestasis is one of the common clinical diseases, usually associated jaundice. At present, it is lack of western medicines to treat cholestasis, while traditional Chinese medicine such as Yin-zhi-huang formula has a significant therapeutic effect on cholestasis and jaundice. In our previous researches of the National Natural Science Foundation of China (NSFC: NO.81373927), results showed that geniposide, the active ingredient in Yin-zhi-huang formula, can simultaneously activate the nuclear receptors CAR and FXR, and then regulate the downstream target genes to maintain homeostasis of bile acids and bilirubin. However, genipin, the metabolic product of geniposide in vivo, can lead to hepatotoxicity. How to use the structural advantages and features of geniposide and avoid its metabolite toxicity to discover novel "CAR+FXR" dual agonists has become the main content of this project. On the basis of clarifying the mechanisms of action of geniposide with the double targets CAR and FXR, the "in silico→in vitro→in vivo" cumulative screening evaluation strategy is applied and the virtual screening based on molecular docking method is adopted. Then systematically evaluate the pharmacy effect and toxicity at cellular level in vitro and animals in vivo is used, in order to obtain the natural active compounds with the double effects of normalizing gallbladder to cure jaundice with the simultaneous activation of "CAR + FXR". This project is expected to find new natural lead compounds for the treatment of cholestasis and jaundice, and also provide a new research idea for the discovery of multi-target therapeutic drugs from traditional Chinese medicine.