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

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...

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Bibliographic Details
Published in:	Communications biology Vol. 4; no. 1; p. 949
Main Authors:	Reyes Romero, Atilio, Lunev, Serjey, Popowicz, Grzegorz M., Calderone, Vito, Gentili, Matteo, Sattler, Michael, Plewka, Jacek, Taube, Michał, Kozak, Maciej, Holak, Tad A., Dömling, Alexander S. S., Groves, Matthew R.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 10-08-2021 Nature Publishing Group Nature Portfolio
Subjects:	631/154 631/57 Allosteric properties Binding sites Biology Biomedical and Life Sciences Dehydrogenases Divergence Enzymatic activity Interfaces Life Sciences Malate dehydrogenase NMR Nuclear magnetic resonance Plasmodium falciparum
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Summary:	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. Romero et al. perform NMR-based screening of 1500 fragments to identify fragments that bind at the oligomeric interface of malate dehydrogenase (MDH). Their study indicates an allosteric mechanism impacting enzymatic activity, paving the way for development of more selective molecules and a starting point for the future development of specific MDH inhibitors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2399-3642 2399-3642
DOI:	10.1038/s42003-021-02442-1