In vitro and in silico PTP-1B inhibition and in vivo antidiabetic activity of semisynthetic moronic acid derivatives

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 8; pp. 2018 - 2022
• Main Authors: Cerón-Romero, Litzia, Paoli, Paolo, Camici, Guido, Flores-Morales, Virginia, Rios, María Yolanda, Ramírez-Espinosa, Juan J., Hidalgo-Figueroa, Sergio, Navarrete-Vázquez, Gabriel, Estrada-Soto, Samuel
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-04-2016
• Subjects: Animals; Blood Glucose - drug effects; Computer Simulation; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - enzymology; Dose-Response Relationship, Drug; Enzyme inhibition; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Molecular docking; Molecular Docking Simulation; Molecular Structure; Moronic acid derivatives; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - chemical synthesis; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; PTP-1B; Rats; Structure-Activity Relationship; Moronic acid derivatives; Enzyme inhibition; PTP-1B; RGKMKULXFZOUPF-BQSMYOSZSA-N; SXYLITRDEAEYTJ-MGPMMZCJSA-N; Diabetes; Molecular docking
• DOI: 10.1016/j.bmcl.2016.02.082
• EISSN: 1464-3405
• ISSN: 0960-894X

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Six derivatives (1–6) of moronic acid were semi-synthesized and their in vitro protein tyrosine phosphatase 1B (PTP-1B) inhibition activity assessed. Derivatives 2 (IC50=10.8±0.5μM) and 6 (IC50=7.5±0.1μM) displayed the most potent inhibitory activity. Therefore, they (50mg/Kg) were tested for their antidiabetic effect in vivo using a non-insulin dependent diabetes mellitus rat model. The results indicated that they decrease plasma glucose levels during all the experiment (p <0.05). Docking analysis of 2 and 6 with PTP-1B orthosteric site A and allosteric site B, showed that 2 had polar and Van der Waals interactions in both sites with Val49, Gln262, Met258, Phe182, Ala217, Ile219 and Gly259, displaying more affinity for site A. Compound 6 showed polar interaction with Gln262 and Van der Waals with Val49, Ile219, Gly259, Arg254, Ala27, Phe52, Met258, Asp48 and Phe182, suggesting that the potential binding site is localized in site B, close to the catalytic site A. Therefore, derivatives 2 and 6 have potential for the development of antidiabetic agents.