3SFK

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM267

Summary for 3SFK

• Entry DOI: 10.2210/pdb3sfk/pdb
• Descriptor: 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)
• Functional Keywords: 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
• Biological source: Plasmodium falciparum 3D7; More
• Cellular location: Mitochondrion inner membrane ; Single-pass membrane protein : Q08210
• Total number of polymer chains: 1
• Total formula weight: 46240.54

Authors

Deng, X.,Phillips, M. (deposition date: 2011-06-13, release date: 2011-07-06, Last modification date: 2023-09-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.95 Å)