Structure-based design and synthesis of small molecule protein-tyrosine phosphatase 1B inhibitors

Zhu Jun Yao, Bin Ye, Xiong Wu Wu, Shaomeng Wang, Li Wu, Zhong Yin Zhang, Terrence R. Burke

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Protein-tyrosine phosphatase (PTP) inhibitors are attractive as potential signal transduction-directed therapeutics which may be useful in the treatment of a variety of diseases. We have previously reported the X-ray structure of 1,1-difluoro-1-(2-naphthalenyl)methyl] phosphonic acid (4) complexed with the human the protein-tyrosine phosphatase 1B (PTP1B) and its use in the design of an analogue which binds with higher affinity within the catalytic site (Burke, T. R., Jr. et al. Biochemistry 1996, 35, 15989). In the current study, new naphthyldifluoromethyl phosphonic acids were designed bearing acidic functionality intended to interact with the PTP1B Arg47, which is situated just outside the catalytic pocket. This residue has been shown previously to provide key interactions with acidic residues of phosphotyrosyl-containing peptide substrates. Consistent with trends predicted by molecular dynamics calculations, the new analogues bound with 7- to 14-fold higher affinity than the parent 4, in principal validating the design rationale. Copyright (C) 1998 Elsevier Science Ltd.

Original languageEnglish (US)
Pages (from-to)1799-1810
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume6
Issue number10
DOIs
StatePublished - Oct 1 1998
Externally publishedYes

Keywords

  • Amino acids and derivatives
  • Mimetics
  • Phosphonic acids and derivatives
  • Phosphorylation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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