5YE8

The crystal structure of Lp-PLA2 in complex with a novel inhibitor

Summary for 5YE8

• Entry DOI: 10.2210/pdb5ye8/pdb
• Descriptor: Platelet-activating factor acetylhydrolase, N-[3,4-bis(fluoranyl)phenyl]methanesulfonamide (3 entities in total)
• Functional Keywords: hydrolase inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 88226.03

Authors

Liu, Q.F.,Xu, Y.C. (deposition date: 2017-09-15, release date: 2018-07-25, Last modification date: 2023-11-22)

Primary citation

Liu, Q.,Huang, F.,Yuan, X.,Wang, K.,Zou, Y.,Shen, J.,Xu, Y.
Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
J. Med. Chem., 60:10231-10244, 2017

PubMed Abstract: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.

PubMed: 29193967
DOI: 10.1021/acs.jmedchem.7b01530

Experimental method

X-RAY DIFFRACTION (1.851 Å)