Discovery and evaluation of the hybrid of bromophenol and saccharide as potent and selective protein tyrosine phosphatase 1B inhibitors

• Published in: European journal of medicinal chemistry Vol. 134; pp. 24 - 33
• Main Authors: Zhang, Renshuai, Yu, Rilei, Xu, Qi, Li, Xiangqian, Luo, Jiao, Jiang, Bo, Wang, Lijun, Guo, Shuju, Wu, Ning, Shi, Dayong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 07.07.2017; Elsevier
• Subjects: Bromophenol; Chemistry, Medicinal; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Halogenation; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Dynamics Simulation; Monosaccharides - chemistry; Monosaccharides - pharmacology; Permeability; Pharmacology & Pharmacy; Phenols - chemistry; Phenols - pharmacology; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism; PTP1B; Saccharide; Science & Technology; Selectivity; Saccharide; Selectivity; PTP1B; Permeability; Bromophenol; PTP1B INHIBITORS; CELLS; DOCKING; ALGA RHODOMELA-CONFERVOIDES; IDENTIFICATION; INSULIN SENSITIVITY; C57BL/KSJ-DB/DB MICE; FRAGMENT; ANTIDIABETIC PROPERTIES; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.04.004

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin signaling pathway. Inhibition of PTP1B is expected to improve insulin action. Appropriate selectivity and permeability are the gold standard for excellent PTP1B inhibitors. In this work, molecular hybridization-based screening identified a selective competitive PTP1B inhibitor. Compound 10a has IC50 values of 199 nM against PTP1B, and shows 32-fold selectivity for PTP1B over the closely related phosphatase TCPTP. Molecule docking and molecular dynamics studies reveal the reason of selectivity for PTP1B over TCPTP. Moreover, the cell permeability and cellular activity of compound 10a are demonstrated respectively. [Display omitted] •The hybrid of bromophenol and saccharide was prepared.•Compound 10a exhibited remarkable selectivity for PTP1B over TCPTP.•Molecule docking and molecular dynamics studies reveal the reason of selectivity.•The cell permeability and cellular activity of compound 10a were demonstrated.