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The X‐ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N ‐phenylbenzamide inhibitor reveals novel binding‐site interactions
Author(s) -
Deng Xiaoyi,
Matthews David,
Rathod Pradipsinh K.,
Phillips Margaret A.
Publication year - 2015
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 37
ISSN - 2053-230X
DOI - 10.1107/s2053230x15000989
Subject(s) - dihydroorotate dehydrogenase , plasmodium falciparum , malaria , biology , biochemistry , binding site , structural biology , enzyme , stereochemistry , antimalarial agent , chemistry , computational biology , immunology
Plasmodium species are protozoan parasites that are the causative agent of malaria. Malaria is a devastating disease, and its treatment and control have been hampered by the propensity of the parasite to become drug‐resistant. Dihydroorotate dehydrogenase (DHODH) has been identified as a promising new target for the development of antimalarial agents. Here, the X‐ray structure of P. falciparum DHODH bound to a potent and selective N ‐phenylbenzamide‐based inhibitor (DSM59) is described at 2.3 Å resolution. The structure elucidates novel binding‐site interactions and shows how conformational flexibility of the enzyme leads to the ability to bind diverse chemical structures with high affinity. This information provides new insight into the design of high‐affinity DHODH inhibitors for the treatment of malaria.