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Structure‐Based Approach To Improve a Small‐Molecule Inhibitor by the Use of a Competitive Peptide Ligand
Author(s) -
Ono Katsuki,
Takeuchi Koh,
Ueda Hiroshi,
Morita Yasuhiro,
Tanimura Ryuji,
Shimada Ichio,
Takahashi Hideo
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201310749
Subject(s) - pharmacophore , chemistry , peptide , ligand (biochemistry) , small molecule , combinatorial chemistry , drug discovery , molecule , computational biology , stereochemistry , receptor , biochemistry , biology , organic chemistry
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.