1D7X

CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A MODIFIED PROLINE SCAFFOLD BASED INHIBITOR.

Summary for 1D7X

• Entry DOI: 10.2210/pdb1d7x/pdb
• Related: 1CQR 1D5J
• Descriptor: STROMELYSIN-1 PRECURSOR, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: mixed alpha beta structure, zinc protease, inhibited, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P08254
• Total number of polymer chains: 2
• Total formula weight: 40025.90

Authors

Cheng, M.Y.,Natchus, M.G.,De, B.,Almstead, N.G.,Pikul, S. (deposition date: 1999-10-20, release date: 2000-10-23, Last modification date: 2024-02-07)

Primary citation

Cheng, M.,De, B.,Almstead, N.G.,Pikul, S.,Dowty, M.E.,Dietsch, C.R.,Dunaway, C.M.,Gu, F.,Hsieh, L.C.,Janusz, M.J.,Taiwo, Y.O.,Natchus, M.G.,Hudlicky, T.,Mandel, M.
Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.
J.Med.Chem., 42:5426-5436, 1999

PubMed Abstract: The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.

PubMed: 10639284
DOI: 10.1021/jm9904699

Experimental method

X-RAY DIFFRACTION (2 Å)