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Discovery of novel scaffolds for Rho kinase 2 inhibitor through TRFRET-based high throughput screening assay.

Abstract
Recent advances in basic and clinical studies have identified Rho kinase (ROCK) as an important target potentially implicated in a variety of cardiovascular diseases and ROCK inhibitors were considered as a pharmacological strategy to prevent and treat cardiovascular diseases. To screen the small molecule compound library against ROCK, a high throughput screening (HTS) campaign was carried out using immobilized metal affinity for phosphochemicals (IMAP)-based time-resolved fluorescence resonance energy transfer (TR-FRET) assay. Z' value and signal to background (S/B) ratio were achieved at 0.76 and 5.27 for the pilot library screening of the most diverse set consisting of 15,040 compounds with a reasonable reconfirmation rate. From this screening campaign, four novel scaffolds, such as 3- nitropyridine, 4-methoxy-1,3,5,-triazine, naphthalene-1,4-dione, and 2,3-dihydro-1H-pyrrolo[2,3-b]quinoxaline, were yielded. Particularly, we found that 3-nitropyridine derivatives possess potent inhibitory activity and selectivity for ROCK. Our findings provide important information for the design of novel ROCK inhibitor.
AuthorsKwang-Seok Oh, Jihye Mun, Jae Eun Cho, Sunghou Lee, Kyu Yang Yi, Chae Jo Lim, Jin Soo Lee, Whui Jung Park, Byung Ho Lee
JournalCombinatorial chemistry & high throughput screening (Comb Chem High Throughput Screen) Vol. 16 Issue 1 Pg. 37-46 (Jan 2013) ISSN: 1875-5402 [Electronic] United Arab Emirates
PMID22934984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • ROCK2 protein, human
  • rho-Associated Kinases
Topics
  • Drug Design
  • Drug Evaluation, Preclinical (methods)
  • High-Throughput Screening Assays (methods)
  • Humans
  • Models, Molecular
  • Protein Kinase Inhibitors (chemistry, pharmacology)
  • Small Molecule Libraries (chemistry, pharmacology)
  • rho-Associated Kinases (antagonists & inhibitors, metabolism)

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