19 F chemical library and 19 F-NMR for a weakly bound complex structure.

Autor:	Shinya S; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Katahira R; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Furuita K; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Sugiki T; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Lee YH; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan.; Research Center for Bioconvergence Analysis, Korea Basic Science Institute Chungbuk 28119 South Korea.; Bio-Analytical Science, University of Science and Technology Daejeon 34113 South Korea.; Graduate School of Analytical Science and Technology, Chungnam National University Daejeon 34134 South Korea., Hattori Y; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Takeshita K; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Nakagawa A; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Kokago A; Graduate School of Engineering Science, Yokohama National University Tokiwadai 79-5, Hodogaya-ku Yokohama 2408501 Japan kojima-chojiro-xk@ynu.ac.jp., Akagi KI; National Institute of Biomedical Innovation, Health and Nutrition 7-6-8 Saito Asagi Ibaraki-city Osaka 567-0085 Japan., Oouchi M; RIKEN Spring-8 Center 1-7-22 Suehiro-cho, Tsurumi-ku Yokohama 230-0045 Japan., Hayashi F; RIKEN Spring-8 Center 1-7-22 Suehiro-cho, Tsurumi-ku Yokohama 230-0045 Japan., Kigawa T; RIKEN Center for Biosystems Dynamics Research 1-7-22 Suehiro-cho, Tsurumi-ku Yokohama 230-0045 Japan., Takimoto-Kamimura M; Quantum-Structural Life Science Laboratories, CBI Research Institute 3-11-1 Shibaura, Minato-ku Tokyo 108-0023 Japan kamimura@cbi-society.org., Fujiwara T; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan., Kojima C; Institute for Protein Research, Osaka University 3-2 Yamadaoka Suita Osaka 565-0871 Japan.; Graduate School of Engineering Science, Yokohama National University Tokiwadai 79-5, Hodogaya-ku Yokohama 2408501 Japan kojima-chojiro-xk@ynu.ac.jp.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2022 Jul 22; Vol. 13 (9), pp. 1100-1111. Date of Electronic Publication: 2022 Jul 22 (Print Publication: 2022).
DOI:	10.1039/d2md00170e
Abstrakt:	Fragment-based drug discovery (FBDD), which involves small compounds <300 Da, has been recognized as one of the most powerful tools for drug discovery. In FBDD, the affinity of hit compounds tends to be low, and the analysis of protein-compound interactions becomes difficult. In an effort to overcome such difficulty, we developed a 19 F-NMR screening method optimizing a 19 F chemical library focusing on highly soluble monomeric molecules. Our method was successfully applied to four proteins, including protein kinases and a membrane protein. For FKBP12, hit compounds were carefully validated by protein thermal shift analysis, 1 H- 15 N HSQC NMR spectroscopy, and isothermal titration calorimetry to determine dissociation constants and model complex structures. It should be noted that the 1 H and 19 F saturation transfer difference experiments were crucial to obtaining highly precise model structures. The combination of 19 F-NMR analysis and the optimized 19 F chemical library enables the modeling of the complex structure made up of a weak binder and its target protein. Competing Interests: There are no conflicts of interest to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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