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Volumn 17, Issue 21, 2007, Pages 5858-5862

A novel class of potent NF-κB signaling inhibitors

Author keywords

Anti inflammatory; Anti viral; Inhibitor; NF B; Nuclear factor B; Signaling

Indexed keywords

BENZIMIDAZOLE DERIVATIVE; I KAPPA B; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; PIPERAZINE DERIVATIVE; PROTEASOME INHIBITOR;

EID: 34548834460     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.08.022     Document Type: Article
Times cited : (27)

References (22)
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    • http://people.bu.edu/gilmore/nf-kb/inhibitors/.
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    • note
    • Virtual screening: proteasome X-ray structure (PDB ID 1IRU) was used for virtual screening due to the sequence identity within the chymotryptic subpocket of the bovine proteasome located on the L and M chain and the human proteasome X and HC5 chains. Protein-ligand docking was used for virtual screening with the binding pocket defined around the catalytically active threonine (THR1) containing the subpockets S1, S2, and S3. Virtual high-throughput screening was done using the docking engine of 4SCan/ProPose (Seifert, M. H.; Wolf, K.; Vitt, D. DDT Biosilico 2003, 1, 143.; Seifert, M. H.; Schmitt, F.; Herz, T.; Kramer, B. J. Mol. Model. 2004, 10, 342) on 4SC's database of five million chemical compounds. The 5000 best docking hits were submitted to filtering: a distance cutoff of 10 Å to THR1 was applied, molecular properties (molecular weight, topological polar surface area, number of rotational bonds) were filtered, unwanted functional groups were omitted, and finally a visual inspection of the docked structures yielded a ranking list. A representative set of 236 compounds was selected for purchasing and biochemical testing.
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    • note
    • 50 values data were fitted to a four parameter logistic function using SigmaPlot.
  • 13
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    • note
    • 4/well and allowed to attach overnight. The cells were subsequently incubated for 5 h with described compounds at 100, 30, 10, 3, 1, 0.3, 0.1, and 0 μM and then stimulated with 10 ng/ml TNF-α for 22 h. The supernatant of the cell was analyzed for SEAP activity using a chemiluminescent SEAP reporter gene assay (Roche, Mannheim, Germany), and a cell viability assay was prepared using a CellTiter-BluTM Cell Viability Assay (Promega, Mannheim, Germany). For each concentration of the compound four replicates were measured.
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    • Know, P.; O'Sullivan, M.; Lentfer, H. Patent application WO 2004/058750, 2004.
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    • All compounds were characterized by MS and NMR (300 MHz) and exhibited satisfactory properties.
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    • Ohnishi, H.; Kosuzume, H.; Mizota M.; Suzuki, Y.; Mochida, E. European patent EP 1984/0116421, 1984.
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    • Fusaka, T.; Ujikawa, O.; Kajiwara, T.; Tanaka, Y, Patent WO9711075, 1997.
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    • Proteasome-Glo™ Cell-Based Assay Technical Bulletin (TB346), 2006 (Promega, Mannheim, Germany).
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    • Leban, J.; Schmitt, H.; Wolf K, Pegoraro S, Wuzik A. US Patent application US 2006/247253, 2006.


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.