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

Atilio Reyes Romero, Serjey Lunev, Grzegorz M Popowicz, Vito Calderone, Matteo Gentili, Michael Sattler, Jacek Plewka, Michał Taube, Maciej Kozak, Tad A Holak, Alexander S S Dömling, Matthew R Groves*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
22 Downloads (Pure)


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.

Original languageEnglish
Article number949
JournalCommunications biology
Issue number1
Publication statusPublished - 10-Aug-2021

Cite this