title: Small and colorful stones make beautiful mosaics: fragment-based chemogenomics.
abstract: Smaller stones with a wide variety of colors make a higher resolution mosaic. In much the same way, smaller chemical entities that are structurally diverse are better able to interrogate protein binding sites. This feature article describes the construction of a diverse fragment library and an analysis of the screening of six representative protein targets belonging to three diverse target classes (G protein-coupled receptors ADRB2, H1R, H3R, and H4R, the ligand-gated ion channel 5-HT3R, and the kinase PKA) using chemogenomics approaches. The integration of experimentally determined bioaffinity profiles across related and unrelated protein targets and chemogenomics analysis of fragment binding and protein structure allow the identification of: (i) unexpected similarities and differences in ligand binding properties, and (ii) subtle ligand affinity and selectivity cliffs. With a wealth of fragment screening data being generated in industry and academia, such approaches will contribute to a more detailed structural understanding of ligand-protein interactions.
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.forename: Gerdien E
authors.initials: GE
authors.lastname: de Kloe
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.forename: Saskia
authors.initials: S
authors.lastname: Nijmeijer
authors.forename: Martien
authors.initials: M
authors.lastname: Kuijer
authors.forename: Mark H P
authors.initials: MH
authors.lastname: Verheij
authors.forename: Paul J
authors.initials: PJ
authors.lastname: England
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: van Muijlwijk-Koezen
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D001665:Binding Sites; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D043562:Receptors, G-Protein-Coupled; D044406:Receptors, Serotonin, 5-HT3; D054852:Small Molecule Libraries; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha