IKKβ inhibitors identification part II: Ligand and structure-based virtual screening

• Published in: Bioorganic & medicinal chemistry 2010-06, Vol.18 (11), p.3951-3960
• Main Authors: Nagarajan, Shanthi, Choo, Hyunah, Cho, Yong Seo, Oh, Kwang-Seok, Lee, Byung Ho, Shin, Kye Jung, Pae, Ae Nim
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Docking; Homology modeling; IkappaB kinase (IKK); IKKβ; Medical sciences; Pharmacology. Drug treatments; Pharmacophore; Virtual screening
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.04.030

IκB kinase (IKK) is critical in proinflammatory cytokine-induced IκBα phosphorylation and subsequent activation of the nuclear transcription factor NF-κB complex. The activated NF-κB plays a major role in the pathogenesis of a number of human disorders, such as rheumatic and chronic inflammatory diseases. The inhibition of NF-κB activation by small molecule inhibitors that targets IKKβ 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 IKKβ 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 IKKβ 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.