8yq8

Quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS V1/S) complexed with FB8, NADPH and dUMP

spinqualitylabelsall models 8yq8, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8yq8 is a 2 chain structure with sequence from Plasmodium falciparum VS/1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.1Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function D9N170_PLAFA Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389] Publication Abstract from PubMed As pregnant women and young children remain the first victims of malaria worldwide, the search for new antimalarials has been focusing on compounds with a high safety profile and extended efficacy. In a previous study, a rigid biphenyl PfDHFR inhibitor was developed by fragment-based screening, displaying sub nM enzyme inhibition but poor antiparasitic activity, presumably due to its low flexibility. Here, we report a new series of compounds that combines the biphenyl fragment with a flexible linker. Interestingly, their mode of binding differs from previously reported compounds, taking advantage of strong hydrophobic interaction. The new flexible biphenyl compounds show overall improved antiparasitic activity compared to rigid ones, with the best compound displaying a 2 nM antiplasmodial IC(50) and suitable drug-like properties. This confirms the importance of compound flexibility for antimalarial activity and opens the way to new opportunities for antimalarial drug design. Novel flexible biphenyl PfDHFR inhibitors with improved antimalarial activity.,Decharuangsilp S, Arwon U, Sooksai N, Rattanajak R, Saeyang T, Vitsupakorn D, Vanichtanankul J, Yuthavong Y, Kamchonwongpaisan S, Hoarau M RSC Med Chem. 2024 May 30;15(7):2496-2507. doi: 10.1039/d4md00197d. eCollection , 2024 Jul 17. PMID:39026651 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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