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.

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.Figure optionsDownload as PowerPoint slide