6M07

Crystal structure of Lp-PLA2 in complex with a novel covalent inhibitor

Summary for 6M07

• Entry DOI: 10.2210/pdb6m07/pdb
• Descriptor: Platelet-activating factor acetylhydrolase, (2S)-2-[(E)-3-[2-(diethylamino)ethyl-[[4-[4-(trifluoromethyl)-2-[2,2,2-tris(fluoranyl)ethoxy]phenyl]phenyl]methyl]amino]-1-oxidanyl-3-oxidanylidene-prop-1-enyl]pyrrolidine-1-carboxylic acid (3 entities in total)
• Functional Keywords: lp-pla2, covalent inhibitor, complex structure, serine phospholipase., hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 85366.93

Authors

Hu, H.C.,Xu, Y.C. (deposition date: 2020-02-20, release date: 2020-12-30, Last modification date: 2024-10-30)

Primary citation

Huang, F.,Hu, H.,Wang, K.,Peng, C.,Xu, W.,Zhang, Y.,Gao, J.,Liu, Y.,Zhou, H.,Huang, R.,Li, M.,Shen, J.,Xu, Y.
Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach.
J.Med.Chem., 63:7052-7065, 2020

PubMed Abstract: Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound , which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.

PubMed: 32459096
DOI: 10.1021/acs.jmedchem.0c00372

Experimental method

X-RAY DIFFRACTION (2.64 Å)