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Reyes Romero, A.* ; Lunev, S.* ; Popowicz, G.M. ; Calderone, V.* ; Gentili, M.* ; Sattler, M. ; Plewka, J.* ; Taube, M.* ; Kozak, M.* ; Holak, T.A.* ; Dömling, A.S.S.* ; Groves, M.R.*

A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity.

Comm. Biol. 4:949 (2021)
Verlagsversion DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Transfer Difference Nmr; Plasmodium-falciparum; Lactate-dehydrogenase; Inhibitors; Protein; Binding; Diffraction; Glycolysis; Scattering; Support
ISSN (print) / ISBN 2399-3642
e-ISSN 2399-3642
Quellenangaben Band: 4, Heft: 1, Seiten: , Artikelnummer: 949 Supplement: ,
Verlag Springer
Verlagsort London
Begutachtungsstatus Peer reviewed
Förderungen National Science Centre (Poland)
European Union