1you: Difference between revisions

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[[Image:1you.gif|left|200px]]<br />

[[Image:1you.gif|left|200px]]<br /><applet load="1you" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="1you" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1you, resolution 2.30Å" />

'''Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor'''<br />

==Overview==

Through the use of computational modeling, a series of, pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead, inhibitor identified through file screening. Incorporation of a biaryl, ether moiety at the C-5 position of the pyrimidinetrione ring resulted in, a dramatic enhancement of MMP-13 potency. Protein crystallography revealed, that this moiety binds in the S(1)(') pocket of the enzyme. Optimization, of the C-4 substituent of the terminal aromatic ring led to incorporation, of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships, of the biaryl ether substituent are presented as is pharmacokinetic data, for a compound that meets our in vitro potency and selectivity goals.

Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.

==About this Structure==

1YOU 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, SO4 and PFD as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1YOU OCA].

1YOU 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>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=PFD:'>PFD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YOU OCA].

==Reference==

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[[Category: metalloprotease]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 20~~:22:~~29 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:07:33 2008''

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@@ Line 1: / Line 1: @@
-[[Image:1you.gif|left|200px]]<br />
+[[Image:1you.gif|left|200px]]<br /><applet load="1you" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1you" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1you, resolution 2.30&Aring;" />
 '''Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor'''<br />
 ==Overview==
-Through the use of computational modeling, a series of, pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead, inhibitor identified through file screening. Incorporation of a biaryl, ether moiety at the C-5 position of the pyrimidinetrione ring resulted in, a dramatic enhancement of MMP-13 potency. Protein crystallography revealed, that this moiety binds in the S(1)(') pocket of the enzyme. Optimization, of the C-4 substituent of the terminal aromatic ring led to incorporation, of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships, of the biaryl ether substituent are presented as is pharmacokinetic data, for a compound that meets our in vitro potency and selectivity goals.
+Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
 ==About this Structure==
-YOU 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, SO4 and PFD as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1YOU OCA].
+YOU 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>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=PFD:'>PFD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YOU OCA].
 ==Reference==
@@ Line 22: / Line 21: @@
 [[Category: metalloprotease]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 20:22:29 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:07:33 2008''