1593090-69-7Relevant academic research and scientific papers
Structure-based approach to improve a small-molecule inhibitor by the use of a competitive peptide ligand
Ono, Katsuki,Takeuchi, Koh,Ueda, Hiroshi,Morita, Yasuhiro,Tanimura, Ryuji,Shimada, Ichio,Takahashi, Hideo
, p. 2597 - 2601 (2014)
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. The best of both worlds: In a structure-based strategy to improve the affinity of a small-molecule inhibitor for its target protein, the interaction mode of a competitive peptide was constructively introduced. Thus, the discrimination of overlapping and non-overlapping peptide-compound pharmacophores by INPHARMA NMR spectroscopy enabled the design of a new compound (see structure) with improved affinity for the platelet receptor glycoprotein VI.
