7KZY

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM778 (3-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)ethyl)-4-(1-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)-1H-pyrrole-2-carboxamide)

7KZY の概要

• エントリーDOI: 10.2210/pdb7kzy/pdb
• 関連するPDBエントリー: 7KYK 7KYV 7KYY 7KZ4
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, 3-methyl-N-[(1R)-1-(5-methyl-1H-pyrazol-3-yl)ethyl]-4-{1-[6-(trifluoromethyl)pyridin-3-yl]cyclopropyl}-1H-pyrrole-2-carboxamide, FLAVIN MONONUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: alpha-beta barrel, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Plasmodium falciparum (isolate 3D7)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 92831.56

構造登録者

Deng, X.,Phillips, M.,Tomchick, D. (登録日: 2020-12-10, 公開日: 2021-05-19, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.75 Å)