9DKO

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM1010 (6-cyclopropyl-2,4-dimethyl-3-(4-(trifluoromethyl)benzyl)-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one)

これはPDB形式変換不可エントリーです。

9DKO の概要

• エントリーDOI: 10.2210/pdb9dko/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, 6-cyclopropyl-2,4-dimethyl-3-{[4-(trifluoromethyl)phenyl]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, FLAVIN MONONUCLEOTIDE, ... (4 entities in total)
• 機能のキーワード: inhibitor, alpha-beta barrel, oxidoreductase, flavoprotein
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46361.73

構造登録者

Deng, X.,Tomchick, D.,Phillips, M. (登録日: 2024-09-09, 公開日: 2025-01-29)

主引用文献

Nie, Z.,Bonnert, R.,Tsien, J.,Deng, X.,Higgs, C.,El Mazouni, F.,Zhang, X.,Li, R.,Ho, N.,Feher, V.,Paulsen, J.,Shackleford, D.M.,Katneni, K.,Chen, G.,Ng, A.C.F.,McInerney, M.,Wang, W.,Saunders, J.,Collins, D.,Yan, D.,Li, P.,Campbell, M.,Patil, R.,Ghoshal, A.,Mondal, P.,Kundu, A.,Chittimalla, R.,Mahadeva, M.,Kokkonda, S.,White, J.,Das, R.,Mukherjee, P.,Angulo-Barturen, I.,Jimenez-Diaz, M.B.,Malmstrom, R.,Lawrenz, M.,Rodriguez-Granillo, A.,Rathod, P.K.,Tomchick, D.R.,Palmer, M.J.,Laleu, B.,Qin, T.,Charman, S.A.,Phillips, M.A.
Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.
J.Med.Chem., 68:590-637, 2025

PubMed Abstract: Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.

PubMed: 39710971
DOI: 10.1021/acs.jmedchem.4c02394

実験手法

X-RAY DIFFRACTION (3 Å)