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.
Supplementary data
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Acknowledgements
The authors thank the Coordination of Improvement of Higher Education (CAPES), the São Paulo Research Foundation (FAPESP), and the National Council of R&D of Brazil (CNPq) for the fellowships granted to the authors. The authors also thank M Maetani and S Schreiber of the Broad Institute of MIT and Harvard, for providing DSM265 for the incubated inhibition assays.
Financial & competing interests disclosure
The authors also thank the Foundation for Research of the State of Rio de Janeiro (FAPERJ), for financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.