IKKβ inhibitors identification part I: Homology model assisted structure based virtual screening

Title
IKKβ inhibitors identification part I: Homology model assisted structure based virtual screening
Authors
샨티무니크말레디추현아조용서오광석이병호배애님
Keywords
IKKb; inflammatory; Virtual screening; Homology modeling; IKKβ; Inhibitor kappa B kinase; Docking; Flex-X; Pharmacophore constraints; Enrichment
Issue Date
2009-04
Publisher
Bioorganic & medicinal chemistry
Citation
VOL 17, NO 7, 2759-2766
Abstract
Control of NF-jB release through the inhibition of IKKb has been identified as a potential target for the treatment of inflammatory and autoimmune diseases. We have employed structure based virtual screening scheme to identify lead like molecule from ChemDiv database. Homology models of IKKb enzyme were developed based on the crystal structures of four kinases. The efficiency of the homology model has been validated at different levels. Docking of known inhibitors library revealed the possible binding mode of inhibitors. Besides, the docking sequence analyses results indicate the responsibility of Glu172 in selectivity. Structure based virtual screening of ChemDiv database has yielded 277 hits. Top scoring 75 compounds were selected and purchased for the IKKb enzyme inhibition test. From the combined approach of virtual screening followed by biological screening, we have identified six novel compounds that can work against IKKb, in which 1 compound had highest inhibition rate 82.09% at 10 lM and IC50 1.76 lM and 5 compounds had 25.35–48.80% inhibition.
URI
http://pubs.kist.re.kr/handle/201004/35798
ISSN
0968-0896
Appears in Collections:
KIST Publication > Article
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