title: Design and synthesis of imidazolidine-2,4-dione derivatives as selective inhibitors by targeting protein tyrosine phosphatase-1B over T-cell protein tyrosine phosphatase.
abstract: Owing to its special role as a negative regulator in both insulin and leptin signaling, protein tyrosine phosphatase-1B (PTP1B) has drawn considerable attention as a target for treating type 2 diabetes and obesity. It, however, is a great challenge to discover inhibitors specific to each PTP due to the highly homologous. In this study, a series of compounds were discovered to inhibit PTP1B based on imidazolidine-2,4-dione by means of 'core hopping'. A selective PTP1B inhibitor (comp#h) was identified, and molecular dynamics simulation and binding free energy calculation were carried out to propose the most likely binding mode of comp#h with PTP1B. The findings reported here may provide a new strategy in discovering selective and effective inhibitors for treating diabetes.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ma
authors.forename: Su-Xia
authors.initials: SX
authors.lastname: Sun
authors.forename: Xian-Chao
authors.initials: XC
authors.lastname: Cheng
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Dong
authors.forename: Run-Ling
authors.initials: RL
authors.lastname: Wang
authors.forename: Wei-Ren
authors.initials: WR
authors.lastname: Xu
mesh_terms: D001665:Binding Sites; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D048289:Imidazolidines; C514490:imidazolidine-2,4-dione; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2
keywords: PTP1B; core hopping; drug design; molecular dynamics; selective inhibitors