Research Article Details
| Article ID: | A02204 |
| PMID: | 34461220 |
| Source: | Pharmacol Res |
| Title: | Identification of the anti-fungal drug fenticonazole nitrate as a novel PPARγ-modulating ligand with good therapeutic index: Structure-based screening and biological validation. |
| Abstract: | In this study, SB-VHTS of the old drug library was conducted to seek for novel PPARγ ligand. In the end, an antifungal drug, FN, was identified in vitro and in vivo as a new and potent PPARγ-modulating ligand to demonstrate significantly anti-diabetic and anti-NAFLD efficacies with minimized side effects induced by PPARγ full agonists TZDs drugs. Further mechanistic investigations revealed that FN showed such desired pharmacological properties mainly through selectively activating the expressions of Adiponectin and GLUT4, effectively promoting the Akt Ser473 phosphorylation, inhibiting the expressions of proinflammatory genes including TNF-α, IL-1β and IL-6 and blocking the PPARγ Ser273 phosphorylation mediated by CDK5 without leading to adipogenesis and increasing the expressions of key adipogenic genes CD36, AP2, LPL, C/EBPα, FASN and PPARγ. Subsequently, a molecular docking study revealed an interesting binding mode between FN and PPARγ LBD including the hydrogen-bonding network among oxygen atom, sulfur atom and nitrogen atom in FN respectively with the PPARγ residues Cys285, Tyr327 and Ser342, which gave proof of concept for the above anti-diabetic action mechanism. Taken together, our findings not only suggest that FN can serve as the new, safe and highly efficacious anti-diabetic and anti-NAFLD agents for clinical use, they can also provide a molecular basis for the future development of PPARγ modulators with a high therapeutic index and the possibility to explore new uses of old drugs for immediate drug discovery. |
| DOI: | 10.1016/j.phrs.2021.105860 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| S07 | Anti-lipogenesis | de novo lipogenesis; de novo lipogenesis; DNL; anti-lipogenic mechanisms; adipogenesis; anti-obesity | stearoyl-CoA desaturase 1 (SCD-1); Acetyl-coenzyme carboxylase; acyl-CoA carboxylase inhibitor (ACC inhibitor); stearoyl Coenzyme A desaturase inhibitor (SCD inhibitor); THR-beta selective agonist; DGAT2 inhibitor; FASN inhibitor | Aramchol; Firsocostat (GS-0976); VK-2809; ION 224 | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D203 | Levothyroxine | Chemical drug | DB00451 | THRA agonist; THRB agonist | Anti-fibrosis | Under clinical trials | Details |
| D366 | Thiazolidinediones | Chemical drug | DB11898 | -- | -- | Under clinical trials | Details |