Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors

Qiufeng Liu; Xinde Chen; Wuyan Chen; Xiaojing Yuan; Haixia Su; Jianhua Shen; Yechun Xu

doi:10.1021/acs.jmedchem.6b00282

Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors

J Med Chem. 2016 May 26;59(10):5115-20. doi: 10.1021/acs.jmedchem.6b00282. Epub 2016 Apr 26.

Authors

Qiufeng Liu¹, Xinde Chen, Wuyan Chen, Xiaojing Yuan, Haixia Su, Jianhua Shen, Yechun Xu

Affiliation

¹ School of Life Science and Technology, ShanghaiTech University , Shanghai 200031, China.

PMID: 27078579
DOI: 10.1021/acs.jmedchem.6b00282

Abstract

Lipoprotein-associated phospholipase A2 (Lp-PLA2) represents a promising therapeutic target for atherosclerosis and Alzheimer's disease. Here we reported the first crystal structures of Lp-PLA2 bound with reversible inhibitors and the thermodynamic characterization of complexes. High rigidity of Lp-PLA2 structure and similar binding modes of inhibitors with completely different scaffolds are revealed. It not only provides the molecular basis for inhibitory activity but also sheds light on the essential features of Lp-PLA2 recognition with reversible inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Alkyl-2-acetylglycerophosphocholine Esterase / antagonists & inhibitors*
1-Alkyl-2-acetylglycerophosphocholine Esterase / chemistry
1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
Dose-Response Relationship, Drug
Drug Design
Humans
Ligands
Models, Molecular
Molecular Structure
Phospholipase A2 Inhibitors / chemical synthesis
Phospholipase A2 Inhibitors / chemistry
Phospholipase A2 Inhibitors / pharmacology*
Structure-Activity Relationship
Thermodynamics*

Substances

Ligands
Phospholipase A2 Inhibitors
1-Alkyl-2-acetylglycerophosphocholine Esterase
PLA2G7 protein, human