Structural insights and mechanistic inhibition of Plasmodium falciparum dihydroorotate dehydrogenase by newly identified chemotypes

Ferulenol inhibits recombinant Plasmodium falciparum dihydroorotate dehydrogenase sub-micromolarly and shows potent asexual blood-stage activity, with its prenylated tail adding hydrophobic interactions.

• Why it matters: Drug resistance threatens malaria control and DSM265 resistance-associated mutations underscore the need for structurally distinct PfDHODH inhibitors with improved potency and selectivity.
• What they did: Target-based high-throughput screening of 432,592 compounds yielded 348 hits, from which seven were prioritized and structurally characterized by X-ray co-crystal structures.
• The result: Co-crystal structures revealed distinct active-site binding modes, and comparative analyses with DSM265 identified binding-site features that may guide next-generation PfDHODH inhibitor design.