6BM7

Crystal structure of Trypanosoma brucei AdoMetDC/prozyme heterodimer in complex with pyrimidineamine inhibitor UTSAM568

6BM7 の概要

• エントリーDOI: 10.2210/pdb6bm7/pdb
• 分子名称: S-adenosylmethionine decarboxylase beta chain, S-adenosylmethionine decarboxylase alpha chain, Inactive S-adenosylmethionine decarboxylase prozyme, ... (9 entities in total)
• 機能のキーワード: adometdc, prozyme, decarboxylase, trypanosoma, inhibitor, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Trypanosoma brucei brucei (strain 927/4 GUTat10.1); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 158233.26

構造登録者

Volkov, O.A.,Chen, Z.,Phillips, M.A. (登録日: 2017-11-13, 公開日: 2018-01-03, 最終更新日: 2024-10-09)

主引用文献

Volkov, O.A.,Brockway, A.J.,Wring, S.A.,Peel, M.,Chen, Z.,Phillips, M.A.,De Brabander, J.K.
Species-Selective Pyrimidineamine Inhibitors of Trypanosoma brucei S-Adenosylmethionine Decarboxylase.
J. Med. Chem., 61:1182-1203, 2018

PubMed Abstract: New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite Trypanosoma brucei. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of T. brucei. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a T. brucei AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for T. brucei AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood-brain barrier penetration. The medicinal chemistry program elucidated structure-activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of TbAdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization.

PubMed: 29271204
DOI: 10.1021/acs.jmedchem.7b01654

実験手法

X-RAY DIFFRACTION (2.98 Å)