 |
PDBsum entry 1d8f
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Design and synthesis of piperazine-Based matrix metalloproteinase inhibitors.
|
|
|
Authors
|
|
M.Cheng,
B.De,
S.Pikul,
N.G.Almstead,
M.G.Natchus,
M.V.Anastasio,
S.J.Mcphail,
C.E.Snider,
Y.O.Taiwo,
L.Chen,
C.M.Dunaway,
F.Gu,
M.E.Dowty,
G.E.Mieling,
M.J.Janusz,
S.Wang-Weigand.
|
|
|
Ref.
|
|
J Med Chem, 2000,
43,
369-380.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
