9DI6
Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM679 (ethyl 1,4-dimethyl-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-3-carboxylate)
This is a non-PDB format compatible entry.
Summary for 9DI6
| Entry DOI | 10.2210/pdb9di6/pdb |
| Descriptor | Dihydroorotate dehydrogenase (quinone), mitochondrial, ethyl 1,4-dimethyl-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrazole-3-carboxylate, FLAVIN MONONUCLEOTIDE, ... (7 entities in total) |
| Functional Keywords | inhibitor, alpha-beta barrel, oxidoreductase, flavoprotein, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Plasmodium falciparum 3D7 |
| Total number of polymer chains | 1 |
| Total formula weight | 46749.20 |
| Authors | Deng, X.,Tomchick, D.,Phillips, M. (deposition date: 2024-09-05, release date: 2025-01-01, Last modification date: 2025-01-29) |
| Primary citation | Nie, Z.,Bonnert, R.,Tsien, J.,Deng, X.,Higgs, C.,El Mazouni, F.,Zhang, X.,Li, R.,Ho, N.,Feher, V.,Paulsen, J.,Shackleford, D.M.,Katneni, K.,Chen, G.,Ng, A.C.F.,McInerney, M.,Wang, W.,Saunders, J.,Collins, D.,Yan, D.,Li, P.,Campbell, M.,Patil, R.,Ghoshal, A.,Mondal, P.,Kundu, A.,Chittimalla, R.,Mahadeva, M.,Kokkonda, S.,White, J.,Das, R.,Mukherjee, P.,Angulo-Barturen, I.,Jimenez-Diaz, M.B.,Malmstrom, R.,Lawrenz, M.,Rodriguez-Granillo, A.,Rathod, P.K.,Tomchick, D.R.,Palmer, M.J.,Laleu, B.,Qin, T.,Charman, S.A.,Phillips, M.A. Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention. J.Med.Chem., 68:590-637, 2025 Cited by PubMed 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 DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM cell 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. PubMed: 39710971DOI: 10.1021/acs.jmedchem.4c02394 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.41 Å) |
Structure validation
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