Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies
| Autor: | Pedro Josué Trejo-Soto, José M. Salas-Pacheco, Marie Jazmin Sarabia-Sanchez, Erick Sierra-Campos, Alfredo Téllez-Valencia, Mónica Valdez-Solana, Daniel Enríquez-Mendiola, José Miguel Velázquez-López, Rafael Castillo, Alicia Hernández-Campos, Carlos Carvente-García, Claudia Avitia-Domínguez |
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| Rok vydání: | 2017 |
| Předmět: |
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Molecular benzimidazole derivatives 0301 basic medicine medicine.medical_treatment Pharmaceutical Science Type 2 diabetes Article Analytical Chemistry Chemical library lcsh:QD241-441 Small Molecule Libraries 03 medical and health sciences chemistry.chemical_compound Insulin resistance lcsh:Organic chemistry Diabetes mellitus Drug Discovery medicine protein tyrosine phosphatase 1B type 2 diabetes enzyme inhibition docking molecular dynamics Hypoglycemic Agents Secretion Physical and Theoretical Chemistry Binding site Protein Tyrosine Phosphatase Non-Receptor Type 1 Insulin Organic Chemistry medicine.disease Kinetics 030104 developmental biology Biochemistry chemistry Chemistry (miscellaneous) Docking (molecular) Thermodynamics Molecular Medicine Benzimidazoles hormones hormone substitutes and hormone antagonists Protein Binding |
| Zdroj: | Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry Molecules, Vol 22, Iss 12, p 2262 (2017) Molecules; Volume 22; Issue 12; Pages: 2262 |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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