A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
10 08 2021
10 08 2021
Historique:
received:
18
02
2021
accepted:
09
07
2021
entrez:
11
8
2021
pubmed:
12
8
2021
medline:
3
9
2021
Statut:
epublish
Résumé
Malate dehydrogenases (MDHs) sustain tumor growth and carbon metabolism by pathogens including Plasmodium falciparum. However, clinical success of MDH inhibitors is absent, as current small molecule approaches targeting the active site are unselective. The presence of an allosteric binding site at oligomeric interface allows the development of more specific inhibitors. To this end we performed a differential NMR-based screening of 1500 fragments to identify fragments that bind at the oligomeric interface. Subsequent biophysical and biochemical experiments of an identified fragment indicate an allosteric mechanism of 4-(3,4-difluorophenyl) thiazol-2-amine (4DT) inhibition by impacting the formation of the active site loop, located >30 Å from the 4DT binding site. Further characterization of the more tractable homolog 4-phenylthiazol-2-amine (4PA) and 16 other derivatives are also reported. These data pave the way for downstream development of more selective molecules by utilizing the oligomeric interfaces showing higher species sequence divergence than the MDH active site.
Identifiants
pubmed: 34376783
doi: 10.1038/s42003-021-02442-1
pii: 10.1038/s42003-021-02442-1
pmc: PMC8355244
doi:
Substances chimiques
Protozoan Proteins
0
Malate Dehydrogenase
EC 1.1.1.37
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
949Informations de copyright
© 2021. The Author(s).
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