title: IKKbeta inhibitors identification part II: ligand and structure-based virtual screening.
abstract: IkappaB kinase (IKK) is critical in proinflammatory cytokine-induced IkappaBalpha phosphorylation and subsequent activation of the nuclear transcription factor NF-kappaB complex. The activated NF-kappaB plays a major role in the pathogenesis of a number of human disorders, such as rheumatic and chronic inflammatory diseases. The inhibition of NF-kappaB activation by small molecule inhibitors that targets IKKbeta may provide a pharmacological basis for interfering with these acute processes. To date, only three inhibitors have passed preclinical trials; on the other hand, identifying novel IKKbeta inhibitors could evolve as potential candidates to meet the clinical requirements in the future. In the present work, we have employed a virtual screening (VS) method to identify novel compounds. The VS scheme is comprised of pharmacophore filtering and, subsequently, receptor based screening. The VS scheme was applied to the databases of 1.04 million compounds to identify three novel compounds that can inhibit the IKKbeta at a micro molar range. Moreover, these compounds can be raised into a potential anti-inflammatory drug candidate after optimizing and passing several phases of clinical trials.
authors.affiliation: Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Nagarajan
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: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Ae Nim
authors.initials: AN
authors.lastname: Pae
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry; D003198:Computer Simulation; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008024:Ligands; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D008024:Ligands; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase