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.