6VTY
Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM483
Summary for 6VTY
| Entry DOI | 10.2210/pdb6vty/pdb |
| Descriptor | Dihydroorotate dehydrogenase (quinone), mitochondrial, ethyl 3,5-dimethyl-4-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrrole-2-carboxylate, FLAVIN MONONUCLEOTIDE, ... (5 entities in total) |
| Functional Keywords | oxidoreductase, mitochondria, alpha-beta barrel |
| Biological source | Plasmodium falciparum (isolate 3D7) |
| Total number of polymer chains | 4 |
| Total formula weight | 199538.27 |
| Authors | Deng, X.,Phillips, M. (deposition date: 2020-02-13, release date: 2020-04-22, Last modification date: 2023-10-11) |
| Primary citation | Kokkonda, S.,Deng, X.,White, K.L.,El Mazouni, F.,White, J.,Shackleford, D.M.,Katneni, K.,Chiu, F.C.K.,Barker, H.,McLaren, J.,Crighton, E.,Chen, G.,Angulo-Barturen, I.,Jimenez-Diaz, M.B.,Ferrer, S.,Huertas-Valentin, L.,Martinez-Martinez, M.S.,Lafuente-Monasterio, M.J.,Chittimalla, R.,Shahi, S.P.,Wittlin, S.,Waterson, D.,Burrows, J.N.,Matthews, D.,Tomchick, D.,Rathod, P.K.,Palmer, M.J.,Charman, S.A.,Phillips, M.A. Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria. J.Med.Chem., 63:4929-4956, 2020 Cited by PubMed Abstract: Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 () showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus DHODH and parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from leading to improved species selectivity versus mammalian enzymes and equivalent activity on and DHODH. The best lead DSM502 () showed efficacy at similar levels of blood exposure to , although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds. PubMed: 32248693DOI: 10.1021/acs.jmedchem.0c00311 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.78 Å) |
Structure validation
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