Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors

Abstract

Dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme that catalyzes fourth reaction of pyrimidine de-novo synthesis. Pyrimidine bases are essential for cellular metabolism and cell growth, and are considered as important precursors used in DNA (thymine and cytosine), RNA (uracil and cytosine), glycoproteins and phospholipids biosynthesis. The significance of pyrimidines biosynthesis in DNA and RNA makes them ideal targets for pharmacological intervention. Inhibitors of DHODH have proven efficacy for the treatment of malaria, autoimmune diseases, cancer, rheumatoid arthritis and psoriasis. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) represents an important target for the treatment of malaria. Many of the clinically relevant anti-tumor and immunosuppressive drugs target human dihydroorotate dehydrogenase (hDHODH), and the two most promising drugs of such kinds are brequinar (antitumor and immunosuppressive) and leflunomide (immunosuppressive). X-ray crystal structures of DHODH in complex with inhibitors reveal common binding region shared by each inhibitor. A number of compounds are identified by high-throughput screening (HTS) of chemical libraries and structure-based computational approaches as selective DHODH inhibitors. Based upon the understanding of molecular interaction of DHODH inhibitors with binding site, some of the common structural features are identified like ability of compounds to interact with ubiquinone (CoQ) binding site and substituents linked to a variety of heterocyclic and heteroaromatic rings responsible for H-bonding with binding site. These findings provide new approaches to design DHODH inhibitors and highlights DHODH as a target for chemotherapeutics. This review is mainly focused on the recent developments in the medicinal chemistry and therapeutic potential of DHODH inhibitors as a target for drug discovery.