5LZ8

Fragment-based inhibitors of Lipoprotein associated Phospholipase A2

Summary for 5LZ8

• Entry DOI: 10.2210/pdb5lz8/pdb
• Descriptor: Platelet-activating factor acetylhydrolase, CHLORIDE ION, 5-[2-[(4~{S})-4-~{tert}-butyl-2-oxidanylidene-pyrrolidin-1-yl]ethoxy]-2-fluoranyl-benzenecarbonitrile, ... (4 entities in total)
• Functional Keywords: lp-pla2 phospholipase, hydrolase, lipid metabolism, inhibitors
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted, extracellular space: Q13093
• Total number of polymer chains: 1
• Total formula weight: 44578.39

Authors

Woolford, A.,Day, P. (deposition date: 2016-09-29, release date: 2016-12-21, Last modification date: 2024-05-08)

Primary citation

Woolford, A.J.,Day, P.J.,Beneton, V.,Berdini, V.,Coyle, J.E.,Dudit, Y.,Grondin, P.,Huet, P.,Lee, L.Y.,Manas, E.S.,McMenamin, R.L.,Murray, C.W.,Page, L.W.,Patel, V.K.,Potvain, F.,Rich, S.J.,Sang, Y.,Somers, D.O.,Trottet, L.,Wan, Z.,Zhang, X.
Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).
J. Med. Chem., 59:10738-10749, 2016

PubMed Abstract: Lp-PLA has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

PubMed: 27933945
DOI: 10.1021/acs.jmedchem.6b01427

Experimental method

X-RAY DIFFRACTION (2.11 Å)