5jdi

Trypanosoma brucei PTR1 in complex with cofactor and inhibitor NMT-H024 (compound 2)

spinqualitylabelsall models 5jdi, resolution 1.38Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5jdi is a 4 chain structure with sequence from Trypanosoma brucei brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.38Å Ligands: 6JO, ACT, CSX, NAP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function O76290_TRYBB Publication Abstract from PubMed Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 muM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 muM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability. Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs.,Borsari C, Luciani R, Pozzi C, Poehner I, Henrich S, Trande M, Cordeiro-da-Silva A, Santarem N, Baptista C, Tait A, Di Pisa F, Dello Iacono L, Landi G, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Gribbon P, Kohler M, Keminer O, Behrens B, Costantino L, Tejera Nevado P, Bifeld E, Eick J, Clos J, Torrado J, Jimenez-Anton MD, Corral MJ, Alunda JM, Pellati F, Wade RC, Ferrari S, Mangani S, Costi MP J Med Chem. 2016 Aug 25;59(16):7598-616. doi: 10.1021/acs.jmedchem.6b00698. Epub , 2016 Aug 5. PMID:27411733 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Pteridine reductase

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