Brequinar derivatives and species-specific drug design for dihydroorotate dehydrogenase.
Therapeutic agents brequinar sodium and leflunomide (Arava) work by binding in a hydrophobic tunnel formed by a highly variable N-terminus of family 2 dihydroorotate dehydrogenase (DHODH). The X-ray crystallographic structure of an analog of brequinar bound to human DHODH was determined. In silico screening of a library of compounds suggested another subset of brequinar analogs that do not inhibit human DHODH as potentially effective inhibitors of Plasmodium falciparum DHODH.
Hurt
Darrell E
DE
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14850, USA.
Sutton
Amanda E
AE
Clardy
Jon
J
D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005486:Flavin Mononucleotide / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D009963:Orotic Acid / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D013045:Species Specificity; D011798:Quinaldines
D001713:Biphenyl Compounds; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D005486:Flavin Mononucleotide; D009963:Orotic Acid; D044925:Oxidoreductases Acting on CH-CH Group Donors; C046943:brequinar; D011798:Quinaldines