title: In vitro and in silico PTP-1B inhibition and in vivo antidiabetic activity of semisynthetic moronic acid derivatives.
abstract: 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 ± 0.5 μM) and 6 (IC50=7.5 ± 0.1 μM) 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.
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico.
authors.forename: Litzia
authors.initials: L
authors.lastname: Cerón-Romero
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche 'Mario Serio', Sezione di Scienze Biochimiche, Universitá degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoli
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche 'Mario Serio', Sezione di Scienze Biochimiche, Universitá degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Camici
authors.affiliation: Unidad Académica de Ciencias Químicas (LSAyB), Universidad Autónoma de Zacatecas Campus Siglo XXI, Carretera Zacatecas-Guadalajara, Km. 6.0, Ejido la Escondida, 98160 Zacatecas, Zacatecas, Mexico.
authors.forename: Virginia
authors.initials: V
authors.lastname: Flores-Morales
authors.affiliation: Centro de Investigaciones Químicas, IICBA, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico.
authors.forename: María Yolanda
authors.initials: MY
authors.lastname: Rios
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Ramírez-Espinosa
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico.
authors.forename: Sergio
authors.initials: S
authors.lastname: Hidalgo-Figueroa
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Navarrete-Vázquez
authors.affiliation: Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Avenida Universidad 1001, Col. Chamilpa, 62209 Cuernavaca, Morelos, Mexico. Electronic address: enoch@uaem.mx.
authors.forename: Samuel
authors.initials: S
authors.lastname: Estrada-Soto
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003198:Computer Simulation; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; C023607:moronic acid; D009828:Oleanolic Acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Diabetes; Enzyme inhibition; Molecular docking; Moronic acid derivatives; PTP-1B