Design and synthesis of non-peptidic inhibitors for the Syk C-terminal SH2 domain based on structure-based in-silico screening.
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.
Niimi
T
T
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
Orita
M
M
Okazawa-Igarashi
M
M
Sakashita
H
H
Kikuchi
K
K
Ball
E
E
Ichikawa
A
A
Yamagiwa
Y
Y
Sakamoto
S
S
Tanaka
A
A
Tsukamoto
S
S
Fujita
S
S
Tatsuta
K
K
Maeda
Y
Y
Chikauchi
K
K
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
D003510:Cyclohexanes; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008314:Malonates; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase