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

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Title: Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention
Authors: Nie, Zhe, Bonnert, Roger, Tsien, Jet, Deng, Xiaoyi, Higgs, Christopher, El Mazouni, Farah, Zhang, Xiaoyu, Li, Renzhe, Ho, Nhi, Feher, Victoria, Paulsen, Janet, Shackleford, David M., Katneni, Kasiram, Chen, Gong, Ng, Alice C. F., McInerney, Mitchell, Wang, Wen, Saunders, Jessica, Collins, Daniel, Yan, Dandan, Li, Peng, Campbell, Michael, Patil, Rahul, Ghoshal, Atanu, Mondal, Pallab, Kundu, Abhijit, Chittimalla, Rajesh, Mahadeva, Muralikumar, Kokkonda, Sreekanth, White, John, Das, Rishi, Mukherjee, Partha, Angulo-Barturen, Iñigo, Jiménez-Díaz, María Belén, Malmstrom, Robert, Lawrenz, Morgan, Rodriguez-Granillo, Agustina, Rathod, Pradipsinh K., Tomchick, Diana R., Palmer, Michael J., Laleu, Benoît, Qin, Tian, Charman, Susan A., Phillips, Margaret A.
Source: Journal of Medicinal Chemistry; January 2025, Vol. 68 Issue: 1 p590-637, 48p
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 PlasmodiumDHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparumcell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.
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  Data: Journal of Medicinal Chemistry; January 2025, Vol. 68 Issue: 1 p590-637, 48p
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  Data: 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 PlasmodiumDHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparumcell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.
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