Brequinar derivatives and species-specific drug design for dihydroorotate dehydrogenase

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 6; pp. 1610 - 1615
• Main Authors: Hurt, Darrell E., Sutton, Amanda E., Clardy, Jon
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.03.2006; Elsevier
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Brequinar; Crystallography, X-Ray; Dihydroorotate dehydrogenase; Drug Design; Enzyme Inhibitors - pharmacology; Flavin Mononucleotide - metabolism; Humans; Hydrogen Bonding; Medical sciences; Orotic Acid - metabolism; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors - chemistry; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Pharmacology. Drug treatments; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Species Specificity; FMN; RrDHODH; PfDHODH; DCIP; HsDHODH; C8E5; Drug design; Brequinar; DCL; Dihydroorotate dehydrogenase; DHODH; Antimalarial; Nitrogen heterocycle; Binding site; Selectivity; Modeling; Antiprotozoal agent; Plasmodium falciparum; Structure activity relation; Carboxylic acid; Chemical compound library; Molecular model; Bicyclic compound; Aromatic compound; Protozoa; Apicomplexa; Enzyme; Benzene derivatives; Enzyme inhibitor; Virtual screening; Inhibitor enzyme complex; X ray diffraction; In vitro; Parasiticide; Carboxamide; Oxidoreductases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.12.029

Brequinar analogs were evaluated through bioassays and in silico screening as species-specific inhibitors of dihydroorotate dehydrogenase (DHODH). A class of analogs known to not inhibit human DHODH dock well to Plasmodium falciparum DHODH. 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.