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PDBsum entry 1no6
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Discovery of a potent, Selective protein tyrosine phosphatase 1b inhibitor using a linked-Fragment strategy.
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Authors
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B.G.Szczepankiewicz,
G.Liu,
P.J.Hajduk,
C.Abad-Zapatero,
Z.Pei,
Z.Xin,
T.H.Lubben,
J.M.Trevillyan,
M.A.Stashko,
S.J.Ballaron,
H.Liang,
F.Huang,
C.W.Hutchins,
S.W.Fesik,
M.R.Jirousek.
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Ref.
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J Am Chem Soc, 2003,
125,
4087-4096.
[DOI no: ]
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PubMed id
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Abstract
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Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the
insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and
the design of small molecule PTP1B inhibitors to treat type II diabetes has
received considerable attention. In this work, NMR-based screening identified a
nonselective competitive inhibitor of PTP1B. A second site ligand was also
identified by NMR-based screening and then linked to the catalytic site ligand
by rational design. X-ray data confirmed that the inhibitor bound with the
catalytic site in the native, "open" conformation. The final compound displayed
excellent potency and good selectivity over many other phosphatases. The modular
approach to drug design described in this work should be applicable for the
design of potent and selective inhibitors of other therapeutically relevant
protein tyrosine phosphatases.
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