2nt7
From Proteopedia
(New page: 200px<br /> <applet load="2nt7" size="450" color="white" frame="true" align="right" spinBox="true" caption="2nt7, resolution 2.1Å" /> '''Crystal structure of...) |
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| - | [[Image:2nt7.gif|left|200px]]<br /> | + | [[Image:2nt7.gif|left|200px]]<br /><applet load="2nt7" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2nt7, resolution 2.1Å" /> | caption="2nt7, resolution 2.1Å" /> | ||
'''Crystal structure of PTP1B-inhibitor complex'''<br /> | '''Crystal structure of PTP1B-inhibitor complex'''<br /> | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Abdominal body fat distribution, modifier of OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176885 176885]], Insulin resistance, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=176885 176885]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2NT7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 902 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http:// | + | 2NT7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=902:'>902</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2NT7 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: ptp1b]] | [[Category: ptp1b]] | ||
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Revision as of 12:58, 23 January 2008
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Crystal structure of PTP1B-inhibitor complex
Overview
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 Structure
2NT7 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Full crystallographic information is available from OCA.
Reference
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 Feb 20;. PMID:17336064
Page seeded by OCA on Wed Jan 23 14:58:29 2008
