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9dlk

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Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM1398 ((S)-3-(amino(3-chloro-4-(trifluoromethyl)phenyl)(cyclopropyl)methyl)-6-cyclopropyl-2-methyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-one)

Structural highlights

9dlk is a 1 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.9Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PYRD_PLAF7 Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.

Publication Abstract from PubMed

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.

Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.,Nie Z, Bonnert R, Tsien J, Deng X, Higgs C, El Mazouni F, Zhang X, Li R, Ho N, Feher V, Paulsen J, Shackleford DM, Katneni K, Chen G, Ng ACF, McInerney M, Wang W, Saunders J, Collins D, Yan D, Li P, Campbell M, Patil R, Ghoshal A, Mondal P, Kundu A, Chittimalla R, Mahadeva M, Kokkonda S, White J, Das R, Mukherjee P, Angulo-Barturen I, Jimenez-Diaz MB, Malmstrom R, Lawrenz M, Rodriguez-Granillo A, Rathod PK, Tomchick DR, Palmer MJ, Laleu B, Qin T, Charman SA, Phillips MA J Med Chem. 2024 Dec 22. doi: 10.1021/acs.jmedchem.4c02394. PMID:39710971^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nie Z, Bonnert R, Tsien J, Deng X, Higgs C, El Mazouni F, Zhang X, Li R, Ho N, Feher V, Paulsen J, Shackleford DM, Katneni K, Chen G, Ng ACF, McInerney M, Wang W, Saunders J, Collins D, Yan D, Li P, Campbell M, Patil R, Ghoshal A, Mondal P, Kundu A, Chittimalla R, Mahadeva M, Kokkonda S, White J, Das R, Mukherjee P, Angulo-Barturen I, Jiménez-Díaz MB, Malmstrom R, Lawrenz M, Rodriguez-Granillo A, Rathod PK, Tomchick DR, Palmer MJ, Laleu B, Qin T, Charman SA, Phillips MA. Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention. J Med Chem. 2024 Dec 22. PMID:39710971 doi:10.1021/acs.jmedchem.4c02394