3SFK

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM267

3SFK の概要

• エントリーDOI: 10.2210/pdb3sfk/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, 2-(1,1-difluoroethyl)-5-methyl-N-[4-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine, FLAVIN MONONUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: alpha beta fold, pyrimidine biosynthesis, flavoprotein, mitochondrion inner membrane, alpha beta barrel oxidoreductase, inhibitor dsm267, fmn, plasmodium falciparum membrane mitochondrion, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Plasmodium falciparum 3D7; 詳細
• 細胞内の位置: Mitochondrion inner membrane ; Single-pass membrane protein : Q08210
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46240.54

構造登録者

Deng, X.,Phillips, M. (登録日: 2011-06-13, 公開日: 2011-07-06, 最終更新日: 2023-09-13)

主引用文献

Coteron, J.M.,Marco, M.,Esquivias, J.,Deng, X.,White, K.L.,White, J.,Koltun, M.,El Mazouni, F.,Kokkonda, S.,Katneni, K.,Bhamidipati, R.,Shackleford, D.M.,Angulo-Barturen, I.,Ferrer, S.B.,Jimenez-Diaz, M.B.,Gamo, F.J.,Goldsmith, E.J.,Charman, W.N.,Bathurst, I.,Floyd, D.,Matthews, D.,Burrows, J.N.,Rathod, P.K.,Charman, S.A.,Phillips, M.A.
Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential.
J.Med.Chem., 54:5540-5561, 2011

PubMed Abstract: Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound toward clinical candidate status.

PubMed: 21696174
DOI: 10.1021/jm200592f

実験手法

X-RAY DIFFRACTION (2.95 Å)