Ligand–Protein Affinity Studies Using Long-Lived States of Fluorine-19 Nuclei

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• 作者：Roberto Buratto ; Daniele Mammoli ; Estel Canet ; Geoffrey Bodenhausen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：1960-1966
• 全文大小：391K
• ISSN：1520-4804

文摘

The lifetimes T_LLS of long-lived states or T_LLC of long-lived coherences can be used for the accurate determination of dissociation constants of weak protein–ligand complexes. The remarkable contrast between signals derived from LLS or LLC in free and bound ligands can be exploited to search for weak binders with large dissociation constants K_D > 1 mM that are important for fragment-based drug discovery but may escape detection by other screening techniques. Alternatively, the high sensitivity of the proposed method can be exploited to work with large ligand-to-protein ratios, with an evident advantage of reduced consumption of precious proteins. The detection of ¹⁹F–¹⁹F long-lived states in suitably designed fluorinated spy molecules allows one to perform competition binding experiments with high sensitivity while avoiding signal overlap that tends to hamper the interpretation of proton spectra of mixtures.