Exploration of molecular interactions between scoparone and associated compounds with Constitutive androstane receptor (CAR) leading to gallstone prevention: an in silico investigation

Scoparone (6, 7 dimethylesculetin) is a biologically active compound derived from the herb <i>Artemisia capillaris</i> having anti-inflammatory, anti-lipemic, and anti-allergic roles. Activation of the constitutive androstane receptor (CAR) in primary hepatocytes of both wild-type and humanized CAR mice by scoparone, accelerates bilirubin and cholesterol clearance <i>in vivo</i>. This can prevent gallstones which is a dreaded gastrointestinal disease. To date, surgery is regarded as the gold standard for treating gallstones. The molecular interactions between scoparone and CAR leading to gallstone prevention are not yet explored. In this study, we have analyzed these interactions through an <i>insilico</i> approach. After extracting the CAR structures (mice and human) from the protein databank and 6, 7-dimethylesuletin from PubChem, energy minimization of both the receptors was done to make them stable followed by docking. Next, a simulation was performed to stabilize the docked complexes. Through docking, H-bonds and pi-pi interactions were found in the complexes, which imply a stable interaction, thus activating the CAR. A similarity search for scoparone was performed and the selected compounds were docked with the CAR receptors. Esculentin acetate and scopoletin acetate interacted with human CAR through pi-alkyl and H-bond respectively. While Fraxidin methyl ether, fraxinol methyl ether, and 6, 7 diethoxycoumarin interacted with mice CAR through H-bond and Pi-Pi T-shaped bonds. The selected complexes were simulated further. Our results are in accordance with the hypothesis in the literature. We have also analyzed the drug likeliness, absorption, non-carcinogenicity, and other properties of scoparone which can support further <i>in vivo</i> studies. Communicated by Ramaswamy H. Sarma

茵陈蒿素（Scoparone，6,7-二甲氧基瑞香素，6,7 dimethylesculetin）是从茵陈蒿（Artemisia capillaris）中提取的生物活性化合物，具有抗炎、降血脂及抗过敏活性。该化合物可激活野生型及人源化组成型雄烷受体（constitutive androstane receptor, CAR）小鼠原代肝细胞内的组成型雄烷受体，在体内加速胆红素与胆固醇的清除，从而预防胆结石这一棘手的胃肠道疾病。迄今为止，手术仍是治疗胆结石的金标准，但茵陈蒿素与组成型雄烷受体之间介导胆结石预防的分子互作机制尚未被阐明。本研究通过计算机模拟（in silico）方法对该分子互作机制展开分析：从蛋白质数据库中获取小鼠与人类的组成型雄烷受体结构，从PubChem数据库获取6,7-二甲氧基瑞香素的结构；随后对两种受体进行能量最小化处理以使其构象稳定，再开展分子对接实验。随后对对接得到的复合物进行分子动力学模拟以稳定其构象。分子对接结果显示，复合物中存在氢键与π-π堆积相互作用，提示二者可形成稳定互作，进而激活组成型雄烷受体。本研究同时对茵陈蒿素开展了相似性搜索，并将筛选得到的化合物与组成型雄烷受体进行分子对接：乙酸瑞香素（Esculentin acetate）与乙酸东莨菪素（scopoletin acetate）分别通过π-烷基相互作用与氢键与人源组成型雄烷受体结合；而香豆素甲醚（Fraxidin methyl ether）、莨菪亭甲醚（fraxinol methyl ether）与6,7-二乙氧基香豆素则分别通过氢键与π-π T型相互作用与小鼠组成型雄烷受体结合。对筛选得到的复合物进一步开展分子动力学模拟，本研究结果与已有文献中的假说相符。本研究同时分析了茵陈蒿素的成药性、吸收性、非致癌性等相关性质，可为后续体内实验提供支撑。本文由Ramaswamy H. Sarma转交刊发。