1YOU: Crystal Structure Of The Catalytic Domain Of Mmp-13 Complexed With A Potent Pyrimidinetrione Inhibitor

Citation:
Abstract
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.
PDB ID: 1YOUDownload
MMDB ID: 32529
PDB Deposition Date: 2005/1/28
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 1YOU: monomeric; determined by author
Molecular Components in 1YOU
Label Count Molecule
Protein (1 molecule)
1
Collagenase 3(Gene symbol: MMP13)
Molecule annotation
Chemicals (6 molecules)
1
2
2
1
3
2
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.