Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

ABSTRACT: Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more poten

SUBMITTER: Nie Z 

PROVIDER: S-EPMC11726676 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature