jm201129m_si_001.pdf (113.94 kB)
Fragment-Based Discovery of Indole Inhibitors of Matrix Metalloproteinase-13
journal contribution
posted on 2011-12-08, 00:00 authored by Steven J. Taylor, Asitha Abeywardane, Shuang Liang, Ingo Muegge, Anil K. Padyana, Zhaoming Xiong, Melissa Hill-Drzewi, Bennett Farmer, Xiang Li, Brandon Collins, John
Xiang Li, Alexander Heim-Riether, John Proudfoot, Qiang Zhang, Daniel Goldberg, Ljiljana Zuvela-Jelaska, Hani Zaher, Jun Li, Neil A. FarrowMatrix 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.