title: Design and synthesis of non-peptidic inhibitors for the Syk C-terminal SH2 domain based on structure-based in-silico screening.
abstract: Structure-based in-silico screening was carried out for the Syk C-terminal SH2 domain. Fragments that could interact with the pY or pY+1 pockets were selected by our in-silico screening. After tethering two fragments bound to these pockets, we have designed and synthesized new compounds that show favorable interaction with the pY+3 pocket. One such compound, having a cyclohexylmalonic acid moiety identified as a novel potent phosphotyrosyl mimetic, exhibited an affinity comparable to that of the monophosphorylated ligand peptide.
authors.affiliation: Department of Applied Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan. tatsuta@mn.waseda.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Niimi
authors.forename: M
authors.initials: M
authors.lastname: Orita
authors.forename: M
authors.initials: M
authors.lastname: Okazawa-Igarashi
authors.forename: H
authors.initials: H
authors.lastname: Sakashita
authors.forename: K
authors.initials: K
authors.lastname: Kikuchi
authors.forename: E
authors.initials: E
authors.lastname: Ball
authors.forename: A
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Yamagiwa
authors.forename: S
authors.initials: S
authors.lastname: Sakamoto
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: S
authors.initials: S
authors.lastname: Fujita
authors.forename: K
authors.initials: K
authors.lastname: Tatsuta
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: K
authors.initials: K
authors.lastname: Chikauchi
mesh_terms: D001667:Binding, Competitive; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008314:Malonates / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D019000:Phosphotyrosine / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000072377:Syk Kinase; D018909:src Homology Domains
chemical_list: D003510:Cyclohexanes; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008314:Malonates; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase