School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian 361002, China.
School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Fujian 361002, China; Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Bioorg Chem. 2019 Apr;85:413-419. doi: 10.1016/j.bioorg.2019.01.007. Epub 2019 Jan 10.
Retinoid X receptor alpha (RXRα), a central member of the nuclear receptor superfamily and a key regulator of many signal transduction pathways, has been an attractive drug target. We previously discovered that an N-terminally truncated form of RXRα can be induced by specific ligands to form homotetramers, which, as a result of conformational selection, forms the basis for inhibiting the nongenomic activation of RXRα. Here, we report the identification and characterization of atorvastatin as a new RXRα tetramer stabilizer by using structure-based virtual screening and demonstrate that virtual library screening can be used to aid in identifying RXRα ligands that can induce its tetramerization. In this study, docking was applied to screen the FDA-approved small molecule drugs in the DrugBank 4.0 collection. Two compounds were selected and purchased for testing. We showed that the selected atorvastatin could bind to RXRα to promote RXRα-LBD tetramerization. We also showed that atorvastatin possessed RXRα-dependent apoptotic effects. In addition, we used a chemical approach to aid in the studies of the binding mode of atorvastatin.
视黄醇 X 受体 α（RXRα）是核受体超家族的核心成员，也是许多信号转导途径的关键调节剂，一直是一个有吸引力的药物靶点。我们之前发现，RXRα 的 N 端截断形式可以被特定配体诱导形成同源四聚体，由于构象选择，这为抑制 RXRα 的非基因组激活奠定了基础。在这里，我们通过基于结构的虚拟筛选鉴定并表征了阿托伐他汀（atorvastatin）是一种新的 RXRα 四聚体稳定剂，并证明虚拟文库筛选可用于辅助鉴定可诱导其四聚化的 RXRα 配体。在这项研究中，对接被应用于筛选 DrugBank 4.0 收藏中的已批准的 FDA 小分子药物。选择了两种化合物进行测试。我们表明，所选的阿托伐他汀（atorvastatin）可以与 RXRα 结合，促进 RXRα-LBD 四聚体化。我们还表明，阿托伐他汀（atorvastatin）具有 RXRα 依赖性凋亡作用。此外，我们使用化学方法辅助研究阿托伐他汀（atorvastatin）的结合模式。
