IKKβ inhibitor identification: a multi-filter driven novel scaffold

BackgroundNuclear factor kappa B (NF-κB) is a chief nuclear transcription factor that controls the transcription of various genes; and its activation is tightly controlled by Inhibitor kappa B kinase (IKK). The irregular transcription of NF-κB has been linked to auto-immune disorders, cancer and other diseases. The IKK complex is composed of three units, IKKα, IKKβ, and the regulatory domain NEMO, of which IKKβ is well understood in the canonical pathway. Therefore, the inhibition of IKKβ by drugs forms the molecular basis for anti-inflammatory drug research.ResultsThe ligand- and structure-based virtual screening (VS) technique has been applied to identify IKKβ inhibitors from the ChemDiv database with 0.7 million compounds. Initially, a 3D-QSAR pharmacophore model has been deployed to greatly reduce the database size. Subsequently, recursive partitioning (RP) and docking filters were used to screen the pharmacophore hits. Finally, 29 compounds were selected for IKKβ enzyme inhibition assay to identify a novel small molecule inhibitor of IKKβ protein.ConclusionsIn the present investigation, we have applied various computational models sequentially to virtually screen the ChemDiv database, and identified a small molecule that has an IC50 value of 20.3μ M. This compound is novel among the known IKKβ inhibitors. Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.

[1]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.

[2]  D B Young,et al.  IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation. , 1997, Science.

[3]  G. Keserű,et al.  Functional virtual screening of estrogen receptor α modulators by FlexX-Pharm , 2005 .

[4]  J. Adams,et al.  Novel IKK inhibitors: β-carbolines , 2003 .

[5]  R. Hersperger,et al.  Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. , 2006, Bioorganic & medicinal chemistry letters.

[6]  Stuart Paine,et al.  Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[7]  Shanthi Nagarajan,et al.  IKKbeta inhibitors identification part I: homology model assisted structure based virtual screening. , 2009, Bioorganic & medicinal chemistry.

[8]  G. De’ath,et al.  CLASSIFICATION AND REGRESSION TREES: A POWERFUL YET SIMPLE TECHNIQUE FOR ECOLOGICAL DATA ANALYSIS , 2000 .

[9]  Jaina Mistry,et al.  A rapid computational filter for cytochrome P450 1A2 inhibition potential of compound libraries. , 2005, Journal of medicinal chemistry.

[10]  C. Homon,et al.  Evolution of the Thienopyridine Class of Inhibitors of IκB Kinase-β: Part I: Hit-to-Lead Strategies , 2006 .

[11]  T. Yoshino,et al.  Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity. , 2004, Bioorganic & medicinal chemistry letters.

[12]  P. Bamborough,et al.  The discovery of 2 -amino -3,5 -diarylbenzamide inhibitors of IKK-α and IKK-β kinases , 2007 .

[13]  Toby Lawrence,et al.  IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. , 2005, Nature.

[14]  N. Munshi,et al.  NF-κB as a Therapeutic Target in Multiple Myeloma* , 2002, The Journal of Biological Chemistry.

[15]  Arup K. Ghose,et al.  Knowledge Based Prediction of Ligand Binding Modes and Rational Inhibitor Design for Kinase Drug Discovery , 2008 .

[16]  Daniel P Vercauteren,et al.  Recursive partitioning for the prediction of cytochromes P450 2D6 and 1A2 inhibition: importance of the quality of the dataset. , 2006, Journal of medicinal chemistry.

[17]  Thomas Lengauer,et al.  Flexible docking under pharmacophore type constraints , 2002, J. Comput. Aided Mol. Des..

[18]  Jeffrey Jie-Lou Liao,et al.  Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. , 2007, Journal of medicinal chemistry.

[19]  K. McIntyre,et al.  Synthesis and structure–activity relationship of imidazo(1,2-a)thieno(3,2-e)pyrazines as IKK-β inhibitors , 2007 .

[20]  Toby Lawrence,et al.  IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation , 2005, Nature.

[21]  H. Choo,et al.  3D QSAR pharmacophore model based on diverse IKKβ inhibitors , 2011, Journal of molecular modeling.

[22]  A. Baldwin,et al.  The I kappa B proteins: multifunctional regulators of Rel/NF-kappa B transcription factors. , 1993, Genes & development.

[23]  H. Choo,et al.  IKKbeta inhibitors identification part II: ligand and structure-based virtual screening. , 2010, Bioorganic & medicinal chemistry.

[24]  Matthias Mann,et al.  IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation , 1997 .

[25]  J. Strnad,et al.  IκB kinase inhibitors for treating autoimmune and inflammatory disorders: potential and challenges , 2007 .

[26]  Christopher Lowe,et al.  A novel series of potent and selective IKK2 inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[27]  K. Ziegelbauer,et al.  Synthesis and structure–activity relationships of novel IKK-β inhibitors. Part 3: Orally active anti-inflammatory agents , 2004 .

[28]  Margaret R. Karagas,et al.  Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of beta distributions , 2008, BMC Bioinformatics.

[29]  Tímea Polgár,et al.  Virtual screening for beta-secretase (BACE1) inhibitors reveals the importance of protonation states at Asp32 and Asp228. , 2005, Journal of medicinal chemistry.

[30]  Inhibition of IKK-2 by 2-[(aminocarbonyl)amino]-5-acetylenyl-3-thiophenecarboxamides. , 2005, Bioorganic & medicinal chemistry letters.

[31]  G. Keserű,et al.  Comparative virtual and experimental high-throughput screening for glycogen synthase kinase-3beta inhibitors. , 2005, Journal of medicinal chemistry.

[32]  Arup K. Ghose,et al.  Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery. , 2008, Journal of medicinal chemistry.

[33]  J. Adams,et al.  Novel IKK inhibitors: beta-carbolines. , 2003, Bioorganic & Medicinal Chemistry Letters.

[34]  BMC Bioinformatics , 2005 .

[35]  K. McIntyre,et al.  Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[36]  H. Oki,et al.  Synthesis and Structure Activity Relationship Studies of Benzothieno[3,2- b ]furan Derivatives as a Novel Class of IKKβ Inhibitors , 2007 .

[37]  Liang-Tsung Huang,et al.  iPTREE-STAB: interpretable decision tree based method for predicting protein stability changes upon mutations , 2007, Bioinform..

[38]  György M. Keserü,et al.  Impact of Ligand Protonation on Virtual Screening against β-Secretase (BACE1) , 2007, J. Chem. Inf. Model..

[39]  N. Munshi,et al.  NF-kappa B as a therapeutic target in multiple myeloma. , 2002, The Journal of biological chemistry.

[40]  Marta Bellini,et al.  Straightforward recursive partitioning model for discarding insoluble compounds in the drug discovery process. , 2008, Journal of medicinal chemistry.

[41]  Evolution of the thienopyridine class of inhibitors of IkappaB kinase-beta: part I: hit-to-lead strategies. , 2006, Journal of medicinal chemistry.

[42]  K. McIntyre,et al.  Synthesis and structure-activity relationship of imidazo(1,2-a)thieno(3,2-e)pyrazines as IKK-beta inhibitors. , 2007, Bioorganic & Medicinal Chemistry Letters.

[43]  P. Bamborough,et al.  The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta kinases. , 2007, Bioorganic & medicinal chemistry letters.

[44]  T. Maniatis,et al.  Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Murcko,et al.  Kinase-likeness and kinase-privileged fragments: toward virtual polypharmacology. , 2008, Journal of medicinal chemistry.