Discoveries Of Nuclear Receptor RXR? And Nur77 Modulators Via Computer-aided Virtual Screening And Preliminary Studies Of Their Anticancer Activities

RXRa and Nur77,two central members of the nuclear receptor superfamily and key regulators of many signal transduction pathways,have been attractive drug targets because of their critical role in the development of cancers.We previously discovered that an N-terminally-cleaved form of RXRa 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 RXRa.In the first part of this thesis,we report the identification and characterization of atorvastatin as a novel RXRa ligand by using structure-based virtual screening and biological testing.We performed a virtual screening of DrugBank 4.0 database targeting the allosteric binding site of RXRa tetramer.Two compounds were selected and purchased for biological evaluation.The results showed that atorvastatin can bind to RXRa as antagonists.Further experiments confirmed that atorvastatin can induce RXRa-LBD tetramerization and have RXRa-dependent anticancer effects.In addition,we used molecular docking and chemical approach to aid in the studies of the binding mode of atorvastatin.Although Nur77 is classified as an orphan receptor,increasing evidences showed that specific small molecules can bind to some grooves on the surface of Nur77 and regulate its nongenomic functions.In the second part of this thesis,we report the identification and characterization of A01 as a novel Nur77 ligand by using structure-based virtual screening and biological testing.We performed a virtual screening of ChemDiv database targeting the surface binding site of Nur77.Ten compounds were selected and purchased for biological evaluation.The results showed that AO I can bind to Nur77 and have Nur77-dependent anticancer effects.Studies with animal model showed that A01 potently inhibited the growth of tumor cells in animals.In addition,we explored the synthesis method of A01 and used molecular docking and molecular dynamic simulation study the binding mode of A01.Through two studies,we not only discovered some novel ligands of RXRa and Nur77 with anticancer potential,but also demonstrated that sturcture-based virtual screening can be used to aid in identifying allosteric ligands targeting non-canonical binding sites of nuclear receptor.In addition,the studies provided good examples for future drug discovery.