Comprehensive Approach of 19F Nuclear Magnetic Resonance, Enzymatic, and in Silico Methods for Site-Specific Hit Selection and Validation of Fragment Molecules that Inhibit Methionine γ-Lyase Activity

Kazuyoshi Ikeda, Yuichiro Kezuka, Takamasa Nonaka, Tomoki Yonezawa, Masanori Osawa, Etsuko Katoh

研究成果: Article査読

抄録

Fragment-based screening using 19F NMR (19F-FS) is an efficient method for exploring seed and lead compounds for drug discovery. Here, we demonstrate the utility and merits of using 19F-FS for methionine γ-lyase-binding fragments, together with a 19F NMR-based competition and mutation assay, as well as enzymatic and in silico methods. 19F NMR-based assays provided useful information on binding between 19F-FS hit fragments and target proteins. Although the 19F-FS and enzymatic assay were weakly correlated, they show that the 19F-FS hit fragments contained compounds with inhibitory activity. Furthermore, we found that in silico calculations partially account for the differences in activity levels between the 19F-FS hits as per NMR analysis. A comprehensive approach combining the 19F-FS and other methods not only identified fragment hits but also distinguished structural differences in chemical groups with diverse activity levels.

本文言語English
ページ(範囲)14299-14310
ページ数12
ジャーナルJournal of Medicinal Chemistry
64
19
DOI
出版ステータスPublished - 2021 10月 14

ASJC Scopus subject areas

  • 分子医療
  • 創薬

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