1g49: Difference between revisions
New page: left|200px<br /> <applet load="1g49" size="450" color="white" frame="true" align="right" spinBox="true" caption="1g49, resolution 1.9Å" /> '''A CARBOXYLIC ACID BA... |
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'''A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3'''<br /> | '''A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
1G49 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 ZN, CA and 111 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] Full crystallographic information is available from [http:// | 1G49 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=ZN:'>ZN</scene>, <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=111:'>111</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1G49 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: zinc protease]] | [[Category: zinc protease]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 15:50:58 2008'' | ||
Revision as of 16:50, 15 February 2008
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A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3
OverviewOverview
A series of hydroxamates was prepared from an aminoproline scaffold and, tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed, SAR for the series is reported for five enzymes within the MMP family, and, a number of inhibitors, such as compound 47, display broad-spectrum, activity with sub-nanomolar potency for some enzymes. Modifications of the, P1' portion of the molecule played a key role in affecting both potency, and selectivity within the MMP family. Longer-chain aliphatic substituents, in this region of the molecule tended to increase potency for MMP-3 and, decrease potency for MMP-1, as exemplified by compounds 48-50, while, aromatic substituents, as in compound 52, generated broad-spectrum, inhibition. The data is rationalized based upon X-ray crystal data which, is also presented. While the in vitro peroral absorption seemed to be less, predictable, it tended to decrease with longer and more hydrophilic, substituents. Finally, a rat model of osteoarthritis was used to evaluate, the efficacy of these compounds, and a direct link was established between, their pharmacokinetics and their in vivo efficacy.
DiseaseDisease
Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[185250]
About this StructureAbout this Structure
1G49 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Stromelysin 1, with EC number 3.4.24.17 Full crystallographic information is available from OCA.
ReferenceReference
Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines., Natchus MG, Bookland RG, De B, Almstead NG, Pikul S, Janusz MJ, Heitmeyer SA, Hookfin EB, Hsieh LC, Dowty ME, Dietsch CR, Patel VS, Garver SM, Gu F, Pokross ME, Mieling GE, Baker TR, Foltz DJ, Peng SX, Bornes DM, Strojnowski MJ, Taiwo YO, J Med Chem. 2000 Dec 28;43(26):4948-63. PMID:11150165
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