6gex

Trypanosoma brucei PTR1 in complex with inhibitor 2h (F246)

spinqualitylabelsall models 6gex, resolution 1.78Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6gex is a 4 chain structure with sequence from Trybb. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, EWK, GOL, NAP Related: 6gck, 6gcl, 6gcp, 6gcq, 6gd0, 6gd4, 6gdo, 6gdp Gene: PTR1 (TRYBB) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 2-amino-benzo[d]thiazole has been identified as new core moiety for the development of improved PTR1 inhibitors and anti-Trypanosomatidic agents. Through a molecular docking approach and the crystal structure of 6-(methylsulfonyl)benzo[d]thiazol-2-amine ternary complex with TbPTR1, 42 new compounds were designed, synthesized and evaluated for their ability to inhibit T. brucei and L. major PTR1 enzymes and in-vitro activity against Trypanosoma brucei and amastigote stage of Leishmania infantum. We identified several 2-amino-benzo[d]thiazole derivatives with improved activity against the enzymes (TbPTR1 IC50 = 0.35 microM; LmPTR1 IC50 = 1.9 microM) and anti-parasitic activity against T. brucei in the low microM range. Ten compounds, with low/sub micromolar inhibitor activity against TbPTR1, were able to potentiate the antiparasitic activity of methotrexate (MTX) when evaluated in combination against T. brucei, with a Potentiating Index (PI) ranging between 1.2 and 2.7. The compound library was profile for an early ADME-Toxicity profile and the compounds showing the best in vitro/enzymatic inhibition properties were selected for progression. 2-amino-N-benzylbenzo[d]thiazole-6-carboxamide (4c), was finally identified as a novel potent and selective anti-trypanocydal agent (EC50 = 7.0 microM) with an overall safe early ADME-Toxicity profile. The pharmacokinetic studies of 4c in BALB/c mice using a hydroxypropyl-beta-cyclodextrin formulation yielded good oral bioavailability, confirming its suitability for progression to in-vivo anti-parasitic studies. Enhancement of benzothiazoles as Pteridine Reductase-1 (PTR1) inhibitors for the treatment of Trypanosomatidic infections.,Linciano P, Pozzi C, Dello Iacono L, di PIsa F, Landi G, Bonucci A, Gul S, Kuzikov M, Ellinger B, Witt G, Santarem N, Baptista C, Franco C, Borsoi Moraes C, Muller W, Wittig U, Luciani R, Sesenna A, Quotadamo A, Ferrari S, Pohner I, Cordeiro-da-Silva A, Mangani S, Costantino L, Costi MP J Med Chem. 2019 Mar 25. doi: 10.1021/acs.jmedchem.8b02021. PMID:30908048 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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