5t0l | pdb_00005t0l

Crystal structure of Toxoplasma gondii TS-DHFR complexed with NADPH, dUMP, PDDF and 5-(4-(3,4-dichlorophenyl)piperazin-1-yl)pyrimidine-2,4-diamine (TRC-15)

spinqualitylabelsall models 5t0l, resolution 3.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5t0l is a 2 chain structure with sequence from Toxgo. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 73X, 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 Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 < 10 muM and >2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach. Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design.,Welsch ME, Zhou J, Gao Y, Yan Y, Porter G, Agnihotri G, Li Y, Lu H, Chen Z, Thomas SB ACS Med Chem Lett. 2016 Sep 17;7(12):1124-1129. eCollection 2016 Dec 8. PMID:27994750 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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