7L0K

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM784 (3-(1-(3-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrole-2-carboxamido)ethyl)-1H-pyrazole-5-carboxamide)

Summary for 7L0K

• Entry DOI: 10.2210/pdb7l0k/pdb
• Related: 7L01
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, 3-{(1R)-1-[(3-methyl-4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrrole-2-carbonyl)amino]ethyl}-1H-pyrazole-5-carboxamide, FLAVIN MONONUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: alpha-beta barrel, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Plasmodium falciparum (isolate 3D7)
• Total number of polymer chains: 2
• Total formula weight: 92837.48

Authors

Deng, X.,Phillips, M.,Tomchick, D. (deposition date: 2020-12-11, release date: 2021-05-19, Last modification date: 2023-10-18)

Primary citation

Palmer, M.J.,Deng, X.,Watts, S.,Krilov, G.,Gerasyuto, A.,Kokkonda, S.,El Mazouni, F.,White, J.,White, K.L.,Striepen, J.,Bath, J.,Schindler, K.A.,Yeo, T.,Shackleford, D.M.,Mok, S.,Deni, I.,Lawong, A.,Huang, A.,Chen, G.,Wang, W.,Jayaseelan, J.,Katneni, K.,Patil, R.,Saunders, J.,Shahi, S.P.,Chittimalla, R.,Angulo-Barturen, I.,Jimenez-Diaz, M.B.,Wittlin, S.,Tumwebaze, P.K.,Rosenthal, P.J.,Cooper, R.A.,Aguiar, A.C.C.,Guido, R.V.C.,Pereira, D.B.,Mittal, N.,Winzeler, E.A.,Tomchick, D.R.,Laleu, B.,Burrows, J.N.,Rathod, P.K.,Fidock, D.A.,Charman, S.A.,Phillips, M.A.
Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.
J.Med.Chem., 64:6085-6136, 2021

PubMed Abstract: Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 () suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity against blood and liver schizont stages and show good efficacy in SCID mouse models. They are equally active against and field isolates and are selective for DHODHs versus mammalian enzymes.

PubMed: 33876936
DOI: 10.1021/acs.jmedchem.1c00173

Experimental method

X-RAY DIFFRACTION (1.96 Å)