Discovery of atorvastatin as a tetramer stabilizer of nuclear receptor RXR? through structure-based virtual screening.

ABSTRACT: Retinoid X receptor alpha (RXR?), 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 RXR? 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 RXR?. Here, we report the identification and characterization of atorvastatin as a new RXR? tetramer stabilizer by using structure-based virtual screening and demonstrate that virtual library screening can be used to aid in identifying RXR? 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 RXR? to promote RXR?-LBD tetramerization. We also showed that atorvastatin possessed RXR?-dependent apoptotic effects. In addition, we used a chemical approach to aid in the studies of the binding mode of atorvastatin.

SUBMITTER: Wang X 

PROVIDER: S-EPMC6447056 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature