Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies

Molecules

卷:22

Erick Sierra-Campos¹  Mónica Valdez-Solana¹  Claudia Avitia-Domínguez²  Daniel Enríquez-Mendiola²  Marie Jazmín Sarabia-Sánchez²  Alfredo Téllez-Valencia²  José Miguel Velázquez-López³  Rafael Castillo³  Carlos Carvente-García³  Pedro Josué Trejo-Soto³  Alicia Hernández-Campos³  José Manuel Salas-Pacheco⁴ 

[1] Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Av. Artículo 123 S/N Fracc. Filadelfia, Gómez Palacio, Durango C.P. 35010, Mexico;

[2] Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa S/N, Durango, Durango C.P. 34000, Mexico;

[3] Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad de México C.P. 04510, Mexico;

[4] Instituto de Investigación Científica, Universidad Juárez del Estado de Durango, Av. Universidad S/N, Durango, Durango C.P. 34000, Mexico;

关键词: protein tyrosine phosphatase 1B;    type 2 diabetes;    benzimidazole derivatives;    enzyme inhibition;    docking;    molecular dynamics;   

DOI  :  10.3390/molecules22122262

来源: DOAJ

【 摘 要 】

The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in the secretion of insulin and a resistance in its target organs. In the search for new antidiabetic drugs, one of the principal strategies consists in promoting the action of insulin. In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B), a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance. In the present work, a chemical library of 250 compounds was evaluated to determine their inhibition capability on the protein PTP1B. Ten molecules inhibited over the 50% of the activity of the PTP1B, the three most potent molecules were selected for its characterization, reporting Ki values of 5.2, 4.2 and 41.3 µM, for compounds 1, 2, and 3, respectively. Docking and molecular dynamics studies revealed that the three inhibitors made interactions with residues at the secondary binding site to phosphate, exclusive for PTP1B. The data reported here support these compounds as hits for the design more potent and selective inhibitors against PTP1B in the search of new antidiabetic treatment.

【 授权许可】

Unknown