1you
From Proteopedia
(New page: 200px<br /> <applet load="1you" size="450" color="white" frame="true" align="right" spinBox="true" caption="1you, resolution 2.30Å" /> '''Crystal structure o...) |
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caption="1you, resolution 2.30Å" /> | caption="1you, resolution 2.30Å" /> | ||
'''Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor'''<br /> | '''Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Through the use of computational modeling, a series of | + | 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== | ==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:// | + | 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== | ==Reference== | ||
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[[Category: metalloprotease]] | [[Category: metalloprotease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:07:33 2008'' |
Revision as of 14:07, 21 February 2008
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Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor
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.
About this Structure
1YOU is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Full crystallographic information is available from OCA.
Reference
Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14., Blagg JA, Noe MC, Wolf-Gouveia LA, Reiter LA, Laird ER, Chang SP, Danley DE, Downs JT, Elliott NC, Eskra JD, Griffiths RJ, Hardink JR, Haugeto AI, Jones CS, Liras JL, Lopresti-Morrow LL, Mitchell PG, Pandit J, Robinson RP, Subramanyam C, Vaughn-Bowser ML, Yocum SA, Bioorg Med Chem Lett. 2005 Apr 1;15(7):1807-10. PMID:15780611
Page seeded by OCA on Thu Feb 21 16:07:33 2008
Categories: Homo sapiens | Single protein | Pandit, J. | CA | PFD | SO4 | ZN | Hydrolase | Metalloprotease
