5M0M

Structure-based evolution of a hybrid steroid series of Autotaxin inhibitors

5M0M の概要

• エントリーDOI: 10.2210/pdb5m0m/pdb
• 分子名称: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, (2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: medicinal chemistry, structure based design, autotaxin, hydrolase
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 100662.48

構造登録者

Keune, W.-J.,Heidebrecht, T.,Perrakis, A. (登録日: 2016-10-05, 公開日: 2017-08-16, 最終更新日: 2024-11-20)

主引用文献

Keune, W.J.,Potjewyd, F.,Heidebrecht, T.,Salgado-Polo, F.,Macdonald, S.J.,Chelvarajan, L.,Abdel Latif, A.,Soman, S.,Morris, A.J.,Watson, A.J.,Jamieson, C.,Perrakis, A.
Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators.
J. Med. Chem., 60:2006-2017, 2017

PubMed Abstract: Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.

PubMed: 28165241
DOI: 10.1021/acs.jmedchem.6b01743

実験手法

X-RAY DIFFRACTION (2.1 Å)