title: Fragment library screening reveals remarkable similarities between the G protein-coupled receptor histamine H₄ and the ion channel serotonin 5-HT₃A.
abstract: A fragment library was screened against the G protein-coupled histamine H(4) receptor (H(4)R) and the ligand-gated ion channel serotonin 5-HT(3A) (5-HT(3A)R). Interestingly, significant overlap was found between H(4)R and 5-HT(3A)R hit sets. The data indicates that dual active H(4)R and 5 HT(3A)R fragments have a higher complexity than the selective compounds which has important implications for chemical genomics approaches. The results of our fragment-based library screening study illustrate similarities in ligand recognition between H(4)R and 5-HT(3A)R and have important consequences for selectivity profiling in ongoing drug discovery efforts on H(4)R and 5-HT(3A)R. The affinity profiles of our fragment screening studies furthermore match the chemical properties of the H(4)R and 5-HT(3A)R binding sites and can be used to define molecular interaction fingerprints to guide the in silico prediction of protein-ligand interactions and structure.
authors.affiliation: Leiden/Amsterdam Center of Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Mark H P
authors.initials: MH
authors.lastname: Verheij
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Gerdien E
authors.initials: GE
authors.lastname: de Kloe
authors.forename: Saskia
authors.initials: S
authors.lastname: Nijmeijer
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Smits
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Saskia
authors.initials: S
authors.lastname: Hulscher
authors.forename: Linda
authors.initials: L
authors.lastname: Silvestri
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: van Muijlwijk-Koezen
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry / Q000494:pharmacology*; D011968:Receptors, Histamine / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D009930:Organic Chemicals; D011968:Receptors, Histamine; D044406:Receptors, Serotonin, 5-HT3; D054852:Small Molecule Libraries