Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13.
Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.
Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877-0368, United States. steven.taylor@boehringeringelheim.com
Steven J
SJ
Taylor
Asitha
A
Abeywardane
Shuang
S
Liang
Ingo
I
Muegge
Anil K
AK
Padyana
Zhaoming
Z
Xiong
Melissa
M
Hill-Drzewi
Bennett
B
Farmer
Xiang
X
Li
Brandon
B
Collins
John Xiang
JX
Li
Alexander
A
Heim-Riether
John
J
Proudfoot
Qiang
Q
Zhang
Daniel
D
Goldberg
Ljiljana
L
Zuvela-Jelaska
Hani
H
Zaher
Jun
J
Li
Neil A
NA
Farrow
D018360:Crystallography, X-Ray; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D053509:Matrix Metalloproteinase 13