Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds.

ABSTRACT: Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure determination of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chemical classes and to accommodate inhibitor modifications during lead optimizati

SUBMITTER: Deng X 

PROVIDER: S-EPMC2785385 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature