title: Selection of fragments for kinase inhibitor design: decoration is key.
abstract: In fragment-based screening, the choice of the best suited fragment hit among the detected hits is crucial for success. In our study, a kinase lead compound was fragmented, the hinge-binding motif extracted as a core fragment, and a minilibrary of five similar compounds with fragment-like properties was selected from our proprietary compound database. The structures of five fragments in complex with transforming growth factor β receptor type 1 kinase domain were determined by X-ray crystallography. Three different binding modes of the fragments are observed that depend on the position and the type of the substitution at the core fragment. The influence of different substituents on the preferred fragment pose was analyzed by various computational approaches. We postulate that the replacement of water molecules leads to the different binding modes.
authors.affiliation: Discovery Technologies, Merck Serono Research, Merck Serono R&D, Merck KGaA , Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Czodrowski
authors.forename: Günter
authors.initials: G
authors.lastname: Hölzemann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Barnickel
authors.forename: Hartmut
authors.initials: H
authors.lastname: Greiner
authors.forename: Djordje
authors.initials: D
authors.lastname: Musil
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D054852:Small Molecule Libraries; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I