1you

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spinqualitylabelsall models 1you, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 ZN, CA, SO4 and PFD 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 Mon Nov 12 20:22:29 2007