Plasmodium falciparum dihydroorotate dehydrogenase: a drug target against malaria.

Abstract

Malaria remains one of the most lethal infectious diseases worldwide, and the most severe form is caused by Plasmodium falciparum. In recent decades, the major challenge to treatment of this disease has been the ability of the protozoan parasite to develop resistance to the drugs that are currently in use. Among P. falciparum enzymes, P. falciparum dihydroorotate dehydrogenase has been identified as an important target in drug discovery. Interference with the activity of this enzyme inhibits de novo pyrimidine biosynthesis and consequently prevents malarial infection. Organic synthesis, x-ray crystallography, high-throughput screening and molecular modeling methods such as molecular docking, quantitative structure-activity relationships, structure-based pharmacophore mapping and molecular dynamics simulations have been applied to the discovery of new inhibitors of P. falciparum dihydroorotate dehydrogenase.

• Authors: Lucas Vb Hoelz, Felipe A Calil, Maria C Nonato, Luiz Cs Pinheiro, Nubia Boechat
• Journal: Future medicinal chemistry (Future Med Chem) Vol. 10 Issue 15 Pg. 1853-1874 (08 01 2018) ISSN: 1756-8927 [Electronic] England
• PMID: 30019917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antimalarials
• Dihydroorotate Dehydrogenase
• Enzyme Inhibitors
• Oxidoreductases Acting on CH-CH Group Donors

Topics

• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Crystallography, X-Ray
• Dihydroorotate Dehydrogenase
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Malaria (drug therapy, metabolism)
• Models, Molecular
• Molecular Structure
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, metabolism)
• Parasitic Sensitivity Tests
• Plasmodium falciparum (drug effects, enzymology)
• Structure-Activity Relationship