title: Toward the discovery of vaccine adjuvants: coupling in silico screening and in vitro analysis of antagonist binding to human and mouse CCR4 receptors.
abstract: BACKGROUND
  Adjuvants enhance or modify an immune response that is made to an antigen. An antagonist of the chemokine CCR4 receptor can display adjuvant-like properties by diminishing the ability of CD4+CD25+ regulatory T cells (Tregs) to down-regulate immune responses.
  
  
  METHODS
  Here, we have used protein modelling to create a plausible chemokine receptor model with the aim of using virtual screening to identify potential small molecule chemokine antagonists. A combination of homology modelling and molecular docking was used to create a model of the CCR4 receptor in order to investigate potential lead compounds that display antagonistic properties. Three-dimensional structure-based virtual screening of the CCR4 receptor identified 116 small molecules that were calculated to have a high affinity for the receptor; these were tested experimentally for CCR4 antagonism. Fifteen of these small molecules were shown to inhibit specifically CCR4-mediated cell migration, including that of CCR4(+) Tregs.
  
  
  CONCLUSIONS
  Our CCR4 antagonists act as adjuvants augmenting human T cell proliferation in an in vitro immune response model and compound SP50 increases T cell and antibody responses in vivo when combined with vaccine antigens of Mycobacterium tuberculosis and Plasmodium yoelii in mice.
authors.affiliation: The Jenner Institute, University of Oxford, Newbury, Berkshire, United Kingdom.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Davies
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.forename: Elma Z
authors.initials: EZ
authors.lastname: Tchilian
authors.forename: Janakiraman
authors.initials: J
authors.lastname: Vani
authors.forename: Melkote S
authors.initials: MS
authors.lastname: Shaila
authors.forename: Emily K
authors.initials: EK
authors.lastname: Forbes
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Draper
authors.forename: Peter C L
authors.initials: PC
authors.lastname: Beverley
authors.forename: David F
authors.initials: DF
authors.lastname: Tough
authors.forename: Darren R
authors.initials: DR
authors.lastname: Flower
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000941:Antigens / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002417:Cattle; D002465:Cell Movement; D019295:Computational Biology / Q000379:methods; D015536:Down-Regulation; D006801:Humans; D066298:In Vitro Techniques; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D010967:Plasmodium yoelii / Q000378:metabolism; D011485:Protein Binding; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D014612:Vaccines / Q000737:chemistry
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D054398:Receptors, CCR4; D014612:Vaccines