2nta: Difference between revisions
New page: left|200px<br /> <applet load="2nta" size="450" color="white" frame="true" align="right" spinBox="true" caption="2nta, resolution 2.1Å" /> '''Crystal Structure of... |
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[[Image:2nta.gif|left|200px]]<br /> | [[Image:2nta.gif|left|200px]]<br /><applet load="2nta" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2nta, resolution 2.1Å" /> | caption="2nta, 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. | ||
==About this Structure== | ==About this Structure== | ||
2NTA 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 521 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:// | 2NTA 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=521:'>521</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=2NTA OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: ptp1b]] | [[Category: ptp1b]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:58:31 2008'' | ||
