2nta: Difference between revisions

Revision as of 09:53, 4 May 2008

Crystal Structure of PTP1B-inhibitor Complex

OverviewOverview

The following account describes our systematic effort to replace one of the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active hits were validated using enzymatic assays before pursuing efforts to improve the potency. Only when the C2 carboxylic acid was replaced with another ionizable functional group was reversible and competitive inhibition retained. Use of a tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to the discovery of two unique starting series that showed improved permeability (PAMPA) and potency of the order of 300nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.

About this StructureAbout this Structure

2NTA is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Probing acid replacements of thiophene PTP1B inhibitors., Wan ZK, Follows B, Kirincich S, Wilson D, Binnun E, Xu W, Joseph-McCarthy D, Wu J, Smith M, Zhang YL, Tam M, Erbe D, Tam S, Saiah E, Lee J, Bioorg Med Chem Lett. 2007 May 15;17(10):2913-20. Epub 2007 Feb 20. PMID:17336064 Page seeded by OCA on Sun May 4 09:53:10 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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 [[Image:2nta.gif|left|200px]]
- {{Structure
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-|LIGAND= <scene name='pdbligand=521:5-(4-CHLORO-5-PHENYL-3-THIENYL)-1,2,5-THIADIAZOLIDIN-3-ONE+1,1-DIOXIDE'>521</scene>
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-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span>
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-|GENE= PTPN1, PTP1B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
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-|RELATEDENTRY=[[2nt7|2NT7]], [[2hcx|2HCX]], [[2hce|2HCE]], [[2hfa|2HFA]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2nta FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2nta OCA], [http://www.ebi.ac.uk/pdbsum/2nta PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2nta RCSB]</span>
-}}
 '''Crystal Structure of PTP1B-inhibitor Complex'''
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 [[Category: Follows, B.]]
 [[Category: Xu, W.]]
-[[Category: protein-inhibitor complex]]
+[[Category: Protein-inhibitor complex]]
-[[Category: ptp1b]]
+[[Category: Ptp1b]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 09:53:10 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:08:02 2008''