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 Artemisia capillaris 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 in vivo. 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 insilico 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 in vivo studies. Communicated by Ramaswamy H. Sarma6,7-二甲氧基香豆素（Scoparone，又名滨蒿内酯）是一种从茵陈蒿（Artemisia capillaris）中提取的生物活性化合物，具有抗炎、抗血脂及抗过敏活性。滨蒿内酯可激活野生型及人源化组成型雄烷受体（constitutive androstane receptor, CAR）小鼠的原代肝细胞中的CAR，从而加速体内胆红素与胆固醇的清除，该作用可预防胆结石这一严重的胃肠道疾病。截至目前，手术仍为治疗胆结石的金标准疗法。目前，关于滨蒿内酯与CAR结合并发挥胆结石预防作用的分子机制尚未得到阐明。本研究采用计算机模拟（in silico）方法对二者的相互作用进行了分析。研究人员首先从蛋白质数据库（Protein Data Bank, PDB）获取小鼠及人源CAR的三维结构，从PubChem数据库获取6,7-二甲氧基香豆素的分子结构，随后对两个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。之后对对接得到的复合物进行分子动力学模拟，以进一步稳定其构象。分子对接结果显示，复合物中存在氢键与π-π相互作用，提示二者结合稳定，可激活CAR。此外，本研究对滨蒿内酯进行了相似性分子搜索，并将筛选得到的化合物与CAR受体进行分子对接。其中，乙酸七叶亭酯与乙酸莨菪亭酯分别通过π-烷基相互作用与氢键与人源CAR结合；而秦皮素甲醚、秦皮醇甲醚及6,7-二乙氧基香豆素则通过氢键与π-π T型相互作用与小鼠CAR结合。对筛选得到的复合物进一步开展了分子动力学模拟。本研究结果与已有文献中的假说相符。此外，本研究还分析了滨蒿内酯的成药性、吸收性、非致癌性等相关性质，可为后续体内实验提供参考依据。本文由Ramaswamy H. Sarma供稿。