Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies

• Published in: Drug development research Vol. 79; no. 2; pp. 70 - 80
• Main Authors: Guzmán‐Ávila, Ricardo, Flores‐Morales, Virginia, Paoli, Paolo, Camici, Guido, Ramírez‐Espinosa, Juan José, Cerón‐Romero, Litzia, Navarrete‐Vázquez, Gabriel, Hidalgo‐Figueroa, Sergio, Yolanda Rios, Maria, Villalobos‐Molina, Rafael, Estrada‐Soto, Samuel
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01-03-2018
• Subjects: Animals; antidiabetic agents; Binding sites; Blood glucose; Blood Glucose - drug effects; Catalysis; Computer Simulation; Derivatives; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Docking; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; In vivo methods and tests; Inhibition; Insulin; Kinases; Male; Mice; Molecular Conformation; Molecular Docking Simulation; Molecular Structure; pentacyclic acid triterpenes; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein-tyrosine-phosphatase; PTP‐1B inhibition; Recombinant Fusion Proteins - metabolism; Signal transduction; Signaling; Triterpenes - chemistry; Triterpenes - pharmacology; Triterpenes - therapeutic use; Tyrosine; Ursolic Acid; ursolic acid derivatives; PTP-1B inhibition; docking; antidiabetic agents; pentacyclic acid triterpenes; ursolic acid derivatives
• ISSN: 0272-4391; 1098-2299
• DOI: 10.1002/ddr.21422

Hit, Lead & Candidate Discovery
Protein tyrosine phosphatase 1B (PTP‐1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin‐signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP‐1B inhibition as main mechanism of action. Furthermore, derivatives 1–7 were submitted in vitro to enzymatic PTP‐1B inhibition being 3, 5, and 7 the most active compounds (IC50 = 5.6, 4.7, and 4.6 μM, respectively). In addition, results were corroborated with in silico docking studies with PTP‐1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of −7.48 Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of −6.43 kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50 mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin‐dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p < .05).