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.
J Med Chem
; 64(19): 14299-14310, 2021 10 14.
Article
de En
| MEDLINE
| ID: mdl-34582207
ABSTRACT
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Carbon-sulfur lyases
/
Résonance magnétique nucléaire biomoléculaire
/
Antienzymes
/
Bibliothèques de petites molécules
/
Dosages enzymatiques
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2021
Type de document:
Article
Pays d'affiliation:
Japon