5IZC

Trypanosoma brucei PTR1 in complex with inhibitor F032

5IZC の概要

• エントリーDOI: 10.2210/pdb5izc/pdb
• 分子名称: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N~2~-[(thiophen-2-yl)methyl]-1,3,4-thiadiazole-2,5-diamine, ... (7 entities in total)
• 機能のキーワード: trypanosoma brucei, pteridine reductase, inhibitor, oxidoreductase
• 由来する生物種: Trypanosoma brucei brucei; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 118438.26

構造登録者

Pozzi, C.,Landi, G.,Di Pisa, F.,Mangani, S. (登録日: 2016-03-25, 公開日: 2017-04-05, 最終更新日: 2024-01-10)

主引用文献

Linciano, P.,Dawson, A.,Pohner, I.,Costa, D.M.,Sa, M.S.,Cordeiro-da-Silva, A.,Luciani, R.,Gul, S.,Witt, G.,Ellinger, B.,Kuzikov, M.,Gribbon, P.,Reinshagen, J.,Wolf, M.,Behrens, B.,Hannaert, V.,Michels, P.A.M.,Nerini, E.,Pozzi, C.,di Pisa, F.,Landi, G.,Santarem, N.,Ferrari, S.,Saxena, P.,Lazzari, S.,Cannazza, G.,Freitas-Junior, L.H.,Moraes, C.B.,Pascoalino, B.S.,Alcantara, L.M.,Bertolacini, C.P.,Fontana, V.,Wittig, U.,Muller, W.,Wade, R.C.,Hunter, W.N.,Mangani, S.,Costantino, L.,Costi, M.P.
Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.
ACS Omega, 2:5666-5683, 2017

PubMed Abstract: Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of PTR1 for activity against (). We solved crystal structures of several PTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of PTR1 with low toxicity. In particular, compound , a biphenyl-thiadiazole-2,5-diamine with IC = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC value. In addition, the antiparasitic activity of the combination of and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti- agents can be obtained.

PubMed: 28983525
DOI: 10.1021/acsomega.7b00473

実験手法

X-RAY DIFFRACTION (1.92 Å)