5TBO

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM421

Summary for 5TBO

• Entry DOI: 10.2210/pdb5tbo/pdb
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, 2-(1,1-difluoroethyl)-5-methyl-N-[6-(trifluoromethyl)pyridin-3-yl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine, FLAVIN MONONUCLEOTIDE, ... (7 entities in total)
• Functional Keywords: oxidoreductase, alpha/beta barrel, fmn, mitochondrial membrane, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Plasmodium falciparum (isolate 3D7)
• Total number of polymer chains: 1
• Total formula weight: 46770.21

Authors

Deng, X.,Phillips, M. (deposition date: 2016-09-12, release date: 2016-09-28, Last modification date: 2023-10-04)

Primary citation

Phillips, M.A.,White, K.L.,Kokkonda, S.,Deng, X.,White, J.,El Mazouni, F.,Marsh, K.,Tomchick, D.R.,Manjalanagara, K.,Rudra, K.R.,Wirjanata, G.,Noviyanti, R.,Price, R.N.,Marfurt, J.,Shackleford, D.M.,Chiu, F.C.,Campbell, M.,Jimenez-Diaz, M.B.,Bazaga, S.F.,Angulo-Barturen, I.,Martinez, M.S.,Lafuente-Monasterio, M.,Kaminsky, W.,Silue, K.,Zeeman, A.M.,Kocken, C.,Leroy, D.,Blasco, B.,Rossignol, E.,Rueckle, T.,Matthews, D.,Burrows, J.N.,Waterson, D.,Palmer, M.J.,Rathod, P.K.,Charman, S.A.
A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria.
ACS Infect Dis, 2:945-957, 2016

PubMed Abstract: The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF-aniline moiety of DSM265 with a series of CF-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

PubMed: 27641613
DOI: 10.1021/acsinfecdis.6b00144

Experimental method

X-RAY DIFFRACTION (2.151 Å)