کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1360602 | 981442 | 2009 | 16 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: High throughput screening of potentially selective MMP-13 exosite inhibitors utilizing a triple-helical FRET substrate High throughput screening of potentially selective MMP-13 exosite inhibitors utilizing a triple-helical FRET substrate](/preview/png/1360602.png)
The major components of the cartilage extracellular matrix are type II collagen and aggrecan. Matrix metalloproteinase 13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). In the present study, a triple-helical FRET substrate has been utilized for high throughput screening (HTS) of MMP-13 with the MLSCN compound library (n ∼ 65,000). Thirty-four compounds from the HTS produced pharmacological dose–response curves. A secondary screen using RP-HPLC validated 25 compounds as MMP-13 inhibitors. Twelve of these compounds were selected for counter-screening with 6 representative MMP family members. Five compounds were found to be broad-spectrum MMP inhibitors, 3 inhibited MMP-13 and one other MMP, and 4 were selective for MMP-13. One of the selective inhibitors was more active against MMP-13 triple-helical peptidase activity compared with single-stranded peptidase activity. Since the THP FRET substrate has distinct conformational features that may interact with MMP secondary binding sites (exosites), novel non-active site-binding inhibitors may be identified via HTS protocols utilizing such assays.
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Journal: Bioorganic & Medicinal Chemistry - Volume 17, Issue 3, 1 February 2009, Pages 990–1005