6n1t

Toxoplasma gondii TS-DHFR in complex with selective inhibitor 3

spinqualitylabelsall models 6n1t, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6n1t is a 2 chain structure with sequence from Toxoplasma gondii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.5Å Ligands: BOD, CB3, NDP, UMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DRTS_TOXGO Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP (By similarity). Publication Abstract from PubMed A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC50 of 1.57 +/- 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development. Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.,Hopper AT, Brockman A, Wise A, Gould J, Barks J, Radke JB, Sibley LD, Zou Y, Thomas S J Med Chem. 2019 Feb 14;62(3):1562-1576. doi: 10.1021/acs.jmedchem.8b01754. Epub , 2019 Jan 24. PMID:30624926 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydrofolate reductase 3D structures

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