Structure‐Based Approach To Improve a Small‐Molecule Inhibitor by the Use of a Competitive Peptide Ligand |
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| Authors: | Dr Katsuki Ono Dr Koh Takeuchi Hiroshi Ueda Yasuhiro Morita Dr Ryuji Tanimura Prof Ichio Shimada Prof Hideo Takahashi |
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| Institution: | 1. Biomedicinal Information Research Center (BIRC), National, Institute of Advanced Industrial Science and Technology (AIST), 2‐3‐26 Aomi, Koto‐ku, Tokyo 135‐0064 (Japan);2. Japan Biological Informatics Consortium (JBIC), 2‐3‐26 Aomi, Koto‐ku, Tokyo 135‐0064 (Japan);3. Toray Branch Office of JBIC, 6‐10‐1 Tebiro, Kamakura‐shi, Kanagawa 248‐8555 (Japan);4. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo 133‐0033 (Japan);5. Graduate School of Medical Life Science, Yokohama City University, 1‐7‐29 Suehirocho, Tsurumi‐ku, Yokohama, Kanagawa 230‐0045 (Japan) |
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| Abstract: | 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. |
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| Keywords: | drug discovery glycoproteins NMR spectroscopy peptides pharmacophores |
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