title: Bidentate inhibitors of protein tyrosine phosphatases.
abstract: CONCLUSIONS
  Protein tyrosine phosphatases (PTPs) are important enzymes that are involved in the regulation of cellular signaling. Evidence accumulated over the years has indicated that PTPs present exciting opportunities for drug discovery against diseases such as diabetes, cancer, autoimmune diseases, and tuberculosis. However, the highly conserved and partially positive charge of the catalytic sites of PTPs is a major challenge in the development of potent and highly selective PTP inhibitors.
  
  
  BACKGROUND
  Here, we examine the strategy of developing bidentate inhibitors for selective inhibition of PTPs. Bidentate inhibitors are small-molecular-weight compounds with the ability to bind to both the active site and a non-conserved secondary phosphate binding site. This secondary phosphate binding site was initially discovered in protein tyrosine phosphatase 1B (PTP1B), and, hence, most of the bidentate inhibitors reported in this review are PTP1B inhibitors.
  
  
  RESULTS
  Although bidentate inhibition is a good strategy for developing potent and selective inhibitors, the cell membrane permeability and pharmacokinetic properties of the inhibitors are also important for successful drug development. In this review, we will also summarize the various efforts made toward the development of phosphotyrosine (pTyr) mimetics for increasing cellular permeability.
  
  
  CONCLUSIONS
  Even though the secondary phosphate binding site was initially found in PTP1B, structural data have shown that a secondary binding site can also be found in other PTPs, albeit with varying degrees of accessibility. Along with improvements in pTyr mimetics, we believe that the future will see an increase in the number of orally bioavailable bidentate inhibitors against the various classes of PTPs.
authors.affiliation: 1 Institute of Chemical and Engineering Sciences , Agency for Science Technology and Research, Singapore, Singapore .
authors.forename: Joo-Leng
authors.initials: JL
authors.lastname: Low
authors.forename: Christina L L
authors.initials: CL
authors.lastname: Chai
authors.forename: Shao Q
authors.initials: SQ
authors.lastname: Yao
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases