Division of Physics for Life Functions, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Division of Structural Biology, Department of Pharmaceutical Sciences, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba, Iwate 028-3694, Japan.
J Med Chem. 2021 Oct 14;64(19):14299-14310. doi: 10.1021/acs.jmedchem.1c00766. Epub 2021 Sep 28.
Fragment-based screening using F NMR (F-FS) is an efficient method for exploring seed and lead compounds for drug discovery. Here, we demonstrate the utility and merits of using F-FS for methionine γ-lyase-binding fragments, together with a F NMR-based competition and mutation assay, as well as enzymatic and methods. F NMR-based assays provided useful information on binding between F-FS hit fragments and target proteins. Although the F-FS and enzymatic assay were weakly correlated, they show that the F-FS hit fragments contained compounds with inhibitory activity. Furthermore, we found that calculations partially account for the differences in activity levels between the F-FS hits as per NMR analysis. A comprehensive approach combining the F-FS and other methods not only identified fragment hits but also distinguished structural differences in chemical groups with diverse activity levels.
基于片段的筛选（Fragment-based Screening，FBS）利用 F NMR（F-FS）是一种高效的方法，可用于探索药物发现的种子和先导化合物。在这里，我们展示了使用 F-FS 来研究甲硫氨酸γ-裂解酶结合片段的实用性和优点，以及基于 F NMR 的竞争和突变测定法、酶测定法和计算方法。基于 F NMR 的测定法为 F-FS 命中片段与靶蛋白之间的结合提供了有用的信息。尽管 F-FS 和酶测定法相关性较弱，但它们表明 F-FS 命中片段包含具有抑制活性的化合物。此外，我们发现，根据 NMR 分析，计算部分解释了 F-FS 命中物之间活性水平的差异。综合应用 F-FS 和其他方法不仅可以鉴定片段命中物，还可以区分具有不同活性水平的化学基团的结构差异。
