Natural and Synthetic Dihydroorotate Dehydrogenase Inhibitors for Therapeutic Applications.

Abstract

Dihydroorotate Dehydrogenase (DHODH) is an important mitochondrial enzyme that plays a key role in the catalysis of an important step in de novo pyrimidine biosynthesis, which in turn supports DNA and RNA production. This enzyme is highly conserved across different organisms, including humans, protozoan parasites, and bacteria, although subtle differences in its structure make it possible to selectively inhibit this enzyme. In recent years, this enzyme has emerged as a promising target in the development of therapeutic agents against different diseases, including cancer, autoimmune diseases, and malaria. Various natural and synthetic compounds have shown promise as inhibitors of this enzyme. While natural inhibitors such as lapachol (1), piperine (5), and baicalein (6) provide a starting point in terms of chemical structure, synthetic inhibitors such as GSK983 (20), Brequinar (21), Teriflunomide (22), Vidofludimus (35), BAY 2402234 (36), and Tenovin (40) achieve high potency and specificity against the human enzyme. In the context of malaria treatment, selective inhibitors such as DSM265 (37), DSM267 (38), and DSM421 (39) selectively inhibit Plasmodium falciparum DHODH with minimal cross-reactivity to the human enzyme. This review outlines the conservation and variability in the structure of this enzyme in different organisms, and the mode of interaction with inhibitors, as well as the different strategies that have been adopted to develop potent and selective inhibitors of this enzyme with minimal side effects in the context of cancer, autoimmune diseases, and malaria treatment.

Abstract as supplied by the indexing source. © the authors / publisher.