title: 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.
authors.affiliation: Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, Republic of Korea.
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Jihye
authors.initials: J
authors.lastname: Mun
authors.forename: Jae Eun
authors.initials: JE
authors.lastname: Cho
authors.forename: Sunghou
authors.initials: S
authors.lastname: Lee
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Chae Jo
authors.initials: CJ
authors.lastname: Lim
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Whui Jung
authors.initials: WJ
authors.lastname: Park
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases