Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.
Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.
Heikkilä
Timo
T
School of Chemistry and the Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK.
Ramsey
Christopher
C
Davies
Matthew
M
Galtier
Christophe
C
Stead
Andrew M W
AM
Johnson
A Peter
AP
Fishwick
Colin W G
CW
Boa
Andrew N
AN
McConkey
Glenn A
GA
D000611:Aminobiphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D017354:Point Mutation; D011485:Protein Binding
D000611:Aminobiphenyl Compounds; D000962:Antimalarials; D002227:Carbazoles; D000090722:Dihydroorotate Dehydrogenase; D009281:Naphthalenes; D044925:Oxidoreductases Acting on CH-CH Group Donors