6GD0
Trypanosoma brucei PTR1 in complex with inhibitor 4g (F133)
Summary for 6GD0
| Entry DOI | 10.2210/pdb6gd0/pdb |
| Related | 6GCK 6GCL 6GCP 6GCQ |
| Descriptor | Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, methyl 1-[4-[[(2-azanyl-1,3-benzothiazol-6-yl)carbonylamino]methyl]phenyl]carbonylpiperidine-4-carboxylate, ... (5 entities in total) |
| Functional Keywords | trypanosoma brucei, pteridine reductase, ptr1, tbptr1, benzothiazole, oxidoreductase |
| Biological source | Trypanosoma brucei brucei |
| Total number of polymer chains | 4 |
| Total formula weight | 127128.45 |
| Authors | Landi, G.,Pozzi, C.,Mangani, S. (deposition date: 2018-04-20, release date: 2019-04-03, Last modification date: 2024-01-17) |
| Primary citation | Linciano, P.,Pozzi, C.,Iacono, L.D.,di Pisa, F.,Landi, G.,Bonucci, A.,Gul, S.,Kuzikov, M.,Ellinger, B.,Witt, G.,Santarem, N.,Baptista, C.,Franco, C.,Moraes, C.B.,Muller, W.,Wittig, U.,Luciani, R.,Sesenna, A.,Quotadamo, A.,Ferrari, S.,Pohner, I.,Cordeiro-da-Silva, A.,Mangani, S.,Costantino, L.,Costi, M.P. Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections. J.Med.Chem., 62:3989-4012, 2019 Cited by PubMed Abstract: 2-Amino-benzo[ d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking and crystallography guided the design and synthesis of 42 new benzothiazoles. The compounds were assessed for Trypanosoma brucei and Leishmania major PTR1 inhibition and in vitro activity against T. brucei and amastigote Leishmania infantum. We identified several 2-amino-benzo[ d]thiazoles with improved enzymatic activity ( TbPTR1 IC = 0.35 μM; LmPTR1 IC = 1.9 μM) and low μM antiparasitic activity against T. brucei. The ten most active compounds against TbPTR1 were able to potentiate the antiparasitic activity of methotrexate when evaluated in combination against T. brucei, with a potentiating index between 1.2 and 2.7. The compound library was profiled for early ADME toxicity, and 2-amino- N-benzylbenzo[ d]thiazole-6-carboxamide (4c) was finally identified as a novel potent, safe, and selective anti-trypanocydal agent (EC = 7.0 μM). Formulation of 4c with hydroxypropyl-β-cyclodextrin yielded good oral bioavailability, encouraging progression to in vivo studies. PubMed: 30908048DOI: 10.1021/acs.jmedchem.8b02021 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.74 Å) |
Structure validation
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