Taylor, Steven J. Abeywardane, Asitha Liang, Shuang Muegge, Ingo Padyana, Anil K. Xiong, Zhaoming Hill-Drzewi, Melissa Farmer, Bennett Li, Xiang Collins, Brandon Li, John Xiang Heim-Riether, Alexander Proudfoot, John Zhang, Qiang Goldberg, Daniel Zuvela-Jelaska, Ljiljana Zaher, Hani Li, Jun Farrow, Neil A. 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. identification;novel interaction pattern;MMP isoforms;cartilage homeostasis;optimization techniques;disease states;Indole Inhibitors;Virtual screening methods;inhibitor 2011-12-08
    https://acs.figshare.com/articles/journal_contribution/Fragment_Based_Discovery_of_Indole_Inhibitors_of_Matrix_Metalloproteinase_13/2573734
10.1021/jm201129m.s001