1YOU

Crystal structure of the catalytic domain of MMP-13 complexed with a potent pyrimidinetrione inhibitor

Summary for 1YOU

• Entry DOI: 10.2210/pdb1you/pdb
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: hydrolase, metalloprotease
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P45452
• Total number of polymer chains: 2
• Total formula weight: 39252.88

Authors

Pandit, J. (deposition date: 2005-01-28, release date: 2005-03-15, Last modification date: 2023-08-23)

Primary citation

Blagg, J.A.,Noe, M.C.,Wolf-Gouveia, L.A.,Reiter, L.A.,Laird, E.R.,Chang, S.P.,Danley, D.E.,Downs, J.T.,Elliott, N.C.,Eskra, J.D.,Griffiths, R.J.,Hardink, J.R.,Haugeto, A.I.,Jones, C.S.,Liras, J.L.,Lopresti-Morrow, L.L.,Mitchell, P.G.,Pandit, J.,Robinson, R.P.,Subramanyam, C.,Vaughn-Bowser, M.L.,Yocum, S.A.
Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14.
Bioorg.Med.Chem.Lett., 15:1807-1810, 2005

PubMed 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.

PubMed: 15780611
DOI: 10.1016/j.bmcl.2005.02.038

Experimental method

X-RAY DIFFRACTION (2.3 Å)