Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies.
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).
['Guzmán-Ávila|Ricardo|R|', 'Flores-Morales|Virginia|V|0000-0003-4540-1011', 'Paoli|Paolo|P|', 'Camici|Guido|G|', 'Ramírez-Espinosa|Juan José|JJ|', 'Cerón-Romero|Litzia|L|', 'Navarrete-Vázquez|Gabriel|G|0000-0001-5344-4762', 'Hidalgo-Figueroa|Sergio|S|', 'Yolanda Rios|Maria|M|', 'Villalobos-Molina|Rafael|R|', 'Estrada-Soto|Samuel|S|0000-0003-1860-0744']
D000818:Animals D001786:Blood Glucose D003198:Computer Simulation D003921:Diabetes Mellitus, Experimental D007004:Hypoglycemic Agents D008297:Male D051379:Mice D008968:Molecular Conformation D062105:Molecular Docking Simulation D015394:Molecular Structure D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 D011993:Recombinant Fusion Proteins D014315:Triterpenes
ursolic acid derivatives antidiabetic agents PTP-1B inhibition docking pentacyclic acid triterpenes