IKKβ inhibitors identification part I: Homology model assisted structure based virtual screening
| Autor: | Yong Seo Cho, Ae Nim Pae, Byung Ho Lee, Munikumar Reddy Doddareddy, Kwang-Seok Oh, Shanthi Nagarajan, Hyunah Choo |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Databases Factual Molecular model Molecular Sequence Data Clinical Biochemistry Drug Evaluation Preclinical Pharmaceutical Science Biochemistry Homology (biology) Structure-Activity Relationship Adenosine Triphosphate Catalytic Domain Drug Discovery Computer Simulation Amino Acid Sequence Homology modeling Protein Kinase Inhibitors Molecular Biology chemistry.chemical_classification Virtual screening biology Chemistry Kinase Organic Chemistry I-kappa B Kinase Enzyme Structural Homology Protein Docking (molecular) Enzyme inhibitor biology.protein Computer-Aided Design Thermodynamics Molecular Medicine Algorithms |
| Zdroj: | Bioorganic & Medicinal Chemistry. 17:2759-2766 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2009.02.041 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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