5tbo | pdb_00005tbo
Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM421
Structural highlights
Function[PYRD_PLAF7] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMedThe emergence of drug resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls, while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria leading to its advancement as a preclinical development candidate. A triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor (DSM421) with improved drug-like properties for treatment and prevention of malaria.,Phillips MA, White KL, Kokkonda S, Deng X, White J, El Mazouni F, Marsh KC, Tomchick DR, Manjalanagara K, Rudra KR, Wirjanata G, Noviyanti R, Price RN, Marfurt J, Shackleford DM, Chiu FC, Campbell M, Jimenez Diaz MB, Ferrer-Bazaga S, Angulo-Barturen I, Martinez-Martinez MS, Lafuente-Monasterio MJ, Kaminsky W, Silue K, Zeeman AM, Kocken C, Leroy D, Blasco B, Rossignol E, Rueckle T, Matthews D, Burrows JN, Waterson D, Palmer MJ, Rathod PK, Charman SA ACS Infect Dis. 2016 Sep 17. PMID:27641613[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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