6GCP

Trypanosoma brucei PTR1 in complex with inhibitor 2d (F186)

6GCP の概要

• エントリーDOI: 10.2210/pdb6gcp/pdb
• 関連するPDBエントリー: 6GCK 6GCL
• 分子名称: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-[(3,4-dichlorophenyl)methylsulfanyl]-1,3-benzothiazol-2-amine, ... (6 entities in total)
• 機能のキーワード: trypanosoma brucei, pteridine reductase, ptr1, tbptr1, benzothiazole, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 127504.36

構造登録者

Pozzi, C.,Landi, G.,Mangani, S. (登録日: 2018-04-18, 公開日: 2019-04-03, 最終更新日: 2024-01-17)

主引用文献

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

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: 30908048
DOI: 10.1021/acs.jmedchem.8b02021

実験手法

X-RAY DIFFRACTION (1.52 Å)