title: IKKbeta inhibitors identification part I: homology model assisted structure based virtual screening.
abstract: Control of NF-kappaB release through the inhibition of IKKbeta 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 IKKbeta 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 IKKbeta enzyme inhibition test. From the combined approach of virtual screening followed by biological screening, we have identified six novel compounds that can work against IKKbeta, in which 1 compound had highest inhibition rate 82.09% at 10 microM and IC(50) 1.76 microM and 5 compounds had 25.35-48.80% inhibition.
authors.affiliation: Center for Chemoinformatics Research, Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Nagarajan
authors.forename: Munikumar reddy
authors.initials: Mr
authors.lastname: Doddareddy
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Yong Seo
authors.initials: YS
authors.lastname: Cho
authors.forename: Kwang-Seok
authors.initials: KS
authors.lastname: Oh
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000465:Algorithms; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D003198:Computer Simulation; D017076:Computer-Aided Design; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D051550:I-kappa B Kinase