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

Abstract 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 < .0...
Source: Drug Development Research - Category: Drugs & Pharmacology Authors: Tags: RESEARCH ARTICLE Source Type: research