Structure-based approach to improve a small-molecule inhibitor by the use of a competitive peptide ligand.
Structural information about the target-compound complex is invaluable in the early stage of drug discovery. In particular, it is important to know into which part of the initial compound additional interaction sites could be introduced to improve its affinity. Herein, we demonstrate that the affinity of a small-molecule inhibitor for its target protein could be successfully improved by the constructive introduction of the interaction mode of a competitive peptide. The strategy involved the discrimination of overlapping and non-overlapping peptide-compound pharmacophores by the use of a ligand-based NMR spectroscopic approach, INPHARMA. The obtained results enabled the design of a new compound with improved affinity for the platelet receptor glycoprotein VI (GPVI). The approach proposed herein efficiently combines the advantages of compounds and peptides for the development of higher-affinity druglike ligands.
Biomedicinal Information Research Center (BIRC), National, Institute of Advanced Industrial Science and Technology (AIST), 2-3-26 Aomi, Koto-ku, Tokyo 135-0064 (Japan); Japan Biological Informatics Consortium (JBIC), 2-3-26 Aomi, Koto-ku, Tokyo 135-0064 (Japan).
Katsuki
K
Ono
Koh
K
Takeuchi
Hiroshi
H
Ueda
Yasuhiro
Y
Morita
Ryuji
R
Tanimura
Ichio
I
Shimada
Hideo
H
Takahashi
D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D008024:Ligands; D010980:Platelet Membrane Glycoproteins; D054852:Small Molecule Libraries; C098341:platelet membrane glycoprotein VI
NMR spectroscopy; drug discovery; glycoproteins; peptides; pharmacophores