1D8F

CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A PIPERAZINE BASED INHIBITOR.

Summary for 1D8F

• Entry DOI: 10.2210/pdb1d8f/pdb
• Related: 1CQR 1D5J 1D7X
• 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: 39784.64

Authors

Cheng, M.Y.,De, B.,Pikul, S.,Almstead, N.G.,Natchus, M.G.,Anastasio, M.V.,McPhail, S.J.,Snider, C.E.,Taiwo, Y.O.,Chen, L.Y. (deposition date: 1999-10-22, release date: 2000-10-23, Last modification date: 2024-02-07)

Primary citation

Cheng, M.,De, B.,Pikul, S.,Almstead, N.G.,Natchus, M.G.,Anastasio, M.V.,McPhail, S.J.,Snider, C.E.,Taiwo, Y.O.,Chen, L.,Dunaway, C.M.,Gu, F.,Dowty, M.E.,Mieling, G.E.,Janusz, M.J.,Wang-Weigand, S.
Design and synthesis of piperazine-based matrix metalloproteinase inhibitors.
J.Med.Chem., 43:369-380, 2000

PubMed Abstract: A new generation of cyclic matrix metalloproteinase (MMP) inhibitors derived from dl-piperazinecarboxylic acid has been described. The design involves: incorporation of hydroxamic acid as the bidentate chelating agent for catalytic Zn(2+), placement of a sulfonamide group at the 1N-position of the piperazine ring to fill the S1' pocket of the enzyme, and finally attachment of diverse functional groups at the 4N-position to optimize potency and peroral absorption. A unique combination of all three elements produced inhibitor 20 with high affinity for MMPs 1, 3, 9, and 13 (24, 18, 1.9, and 1.3 nM, respectively). X-ray crystallography data obtained for MMP-3 cocrystallized with 20 gave detailed information on key binding interactions defining an overall scaffold geometry for piperazine-based MMP inhibitors.

PubMed: 10669564
DOI: 10.1021/jm990366q

Experimental method

X-RAY DIFFRACTION (2.4 Å)