5FI8

Crystal structure of plasmodium falciparum dihydroorotate dehydrogenase bounded with DSM422 (Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidine)

5FI8 の概要

• エントリーDOI: 10.2210/pdb5fi8/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, 2-[1,1-bis(fluoranyl)ethyl]-~{N}-[(2~{S})-7-bromanyl-1,2,3,4-tetrahydronaphthalen-2-yl]-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, FLAVIN MONONUCLEOTIDE, ... (6 entities in total)
• 機能のキーワード: fmn, alpha/beta barrel, inhibitor, oxidoreductase / 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: 1
• 化学式量合計: 46650.03

構造登録者

Deng, X.,Kokkonda, S.,Tomchick, D.,Phillips, M. (登録日: 2015-12-22, 公開日: 2016-05-18, 最終更新日: 2023-09-27)

主引用文献

Kokkonda, S.,Deng, X.,White, K.L.,Coteron, J.M.,Marco, M.,de Las Heras, L.,White, J.,El Mazouni, F.,Tomchick, D.R.,Manjalanagara, K.,Rudra, K.R.,Chen, G.,Morizzi, J.,Ryan, E.,Kaminsky, W.,Leroy, D.,Martinez-Martinez, M.S.,Jimenez-Diaz, M.B.,Bazaga, S.F.,Angulo-Barturen, I.,Waterson, D.,Burrows, J.N.,Matthews, D.,Charman, S.A.,Phillips, M.A.,Rathod, P.K.
Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity.
J.Med.Chem., 59:5416-5431, 2016

PubMed Abstract: Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the P. falciparum SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than 1, they most likely would need to be part of a multidose regimen.

PubMed: 27127993
DOI: 10.1021/acs.jmedchem.6b00275

実験手法

X-RAY DIFFRACTION (2.32 Å)