Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention DOI Creative Commons
Zhe Nie, Roger V. Bonnert, Jet Tsien

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 68(1), P. 590 - 637

Published: Dec. 23, 2024

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as target for prevention of malaria through human studies with DSM265, but currently no drugs against this in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, selective pyrazole-based Plasmodium DHODH inhibitors scaffold hop from pyrrole-based series. Optimized compounds were identified low nM-to-pM falciparum cell potency oral activity humanized SCID mouse infection model. The lead compound DSM1465 is more potent has improved absorption, distribution, metabolism excretion/pharmacokinetic (ADME/PK) properties compared DSM265 that support the potential once-monthly chemoprevention at dose. This meets objective identifying be monthly Africa elimination efforts.

Language: Английский

Correction: Chemoprevention of malaria with long-acting oral and injectable drugs: an updated target product profile DOI Creative Commons
Myriam El Gaaloul, André-Marie Tchouatieu, Kassoum Kayentao

et al.

Malaria Journal, Journal Year: 2024, Volume and Issue: 23(1)

Published: Nov. 29, 2024

Language: Английский

Citations

0
Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention DOI Creative Commons
Zhe Nie, Roger V. Bonnert, Jet Tsien

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 68(1), P. 590 - 637

Published: Dec. 23, 2024

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as target for prevention of malaria through human studies with DSM265, but currently no drugs against this in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, selective pyrazole-based Plasmodium DHODH inhibitors scaffold hop from pyrrole-based series. Optimized compounds were identified low nM-to-pM falciparum cell potency oral activity humanized SCID mouse infection model. The lead compound DSM1465 is more potent has improved absorption, distribution, metabolism excretion/pharmacokinetic (ADME/PK) properties compared DSM265 that support the potential once-monthly chemoprevention at dose. This meets objective identifying be monthly Africa elimination efforts.

Language: Английский

Citations

0