6VTY

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM483

6VTY の概要

• エントリーDOI: 10.2210/pdb6vty/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, ethyl 3,5-dimethyl-4-{[4-(trifluoromethyl)phenyl]methyl}-1H-pyrrole-2-carboxylate, FLAVIN MONONUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: oxidoreductase, mitochondria, alpha-beta barrel
• 由来する生物種: Plasmodium falciparum (isolate 3D7)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 199538.27

構造登録者

Deng, X.,Phillips, M. (登録日: 2020-02-13, 公開日: 2020-04-22, 最終更新日: 2023-10-11)

主引用文献

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

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: 32248693
DOI: 10.1021/acs.jmedchem.0c00311

実験手法

X-RAY DIFFRACTION (1.78 Å)