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

Autor:	Tomoki Yonezawa, Yuichiro Kezuka, Kazuyoshi Ikeda, Etsuko Katoh, Masanori Osawa, Takamasa Nonaka
Rok vydání:	2021
Předmět:	chemistry.chemical_classification Mutation Methionine Drug discovery In silico Fluorine-19 NMR medicine.disease_cause chemistry.chemical_compound Enzyme chemistry Biochemistry Drug Discovery medicine Molecular Medicine Hit selection Lyase activity
Zdroj:	Journal of Medicinal Chemistry. 64:14299-14310
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.1c00766
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::8085b52b772fecf7881f9777df91d298 https://doi.org/10.1021/acs.jmedchem.1c00766 Zobrazit plný text záznamu