Raloxifene-driven benzothiophene derivatives: Discovery, structural refinement, and biological evaluation as potent PPARγ modulators based on drug repurposing

By virtue of the drug repurposing strategy, the anti-osteoporosis drug raloxifene was identified as a novel PPARγ ligand through structure-based virtual high throughput screening (SB-VHTS) of FDA-approved drugs and TR-FRET competitive binding assay. Subsequent structural refinement of raloxifene led to the synthesis of a benzothiophene derivative, YGL-12. This compound exhibited potent PPARγ modulation with partial agonism, uniquely promoting Adiponectin expression and inhibiting PPARγ Ser273 phosphorylation by CDK5 without inducing the expression of adipongenesis associated genes, including PPARγ, aP2, CD36, FASN and C/EBPα. This specific activity profile resulted in effective hypoglycemic properties, avoiding major TZD-related adverse effects like weight gain and hepatomegaly, which were demonstrated in db/db mice. Molecular docking studies showed that YGL-12 established additional hydrogen bonds with Ile281 and enhanced hydrogen-bond interaction with Ser289 as well as PPARγ Ser273 phosphorylation-related residues Ser342 and Glu343. These findings suggested YGL-12 as a promising T2DM therapeutic candidate, thereby providing a molecular framework for the development of novel PPARγ modulators with an enhanced therapeutic index.

(S)-VSP-77 (PubChem CID; ); 139267749); 16131098; 3-Isobutyl-1-methylxanthine (PubChem CID: 3758); 5743); Benzothiophene derivatives; Dexamethasone (PubChem CID; Dimethyl sulfoxide (PubChem CID: 679); Glucose (PubChem CID:5793); Insulin (PubChem CID:; PPARγ Ser273 phosphorylation; Raloxifene (PubChem CID:5035); Rosiglitazone (PubChem CID: 77999); SPPARγM; Structural optimization; Structure-based virtual screening; T2DM.