Fragment-Based Discovery of Indole Inhibitors of Matrix Metalloproteinase-13
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- 作者：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. Farrow
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：December 8, 2011
- 年：2011
- 卷：54
- 期：23
- 页码：8174-8187
- 全文大小：596K
- 年卷期：v.54,no.23(December 8, 2011)
- ISSN：1520-4804
文摘
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鈥?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.