Development of an Activity-Based Probe and In Silico Design Reveal Highly Selective Inhibitors for Diacylglycerol Lipase-α in Brain

• Published in: Angewandte Chemie International Edition 2013-11, Vol.52 (46), p.12081-12085
• Main Authors: Baggelaar, Marc P., Janssen, Freek J., van Esbroeck, Annelot C. M., den Dulk, Hans, Allarà, Marco, Hoogendoorn, Sascha, McGuire, Ross, Florea, Bogdan I., Meeuwenoord, Nico, van den Elst, Hans, van der Marel, Gijsbert A., Brouwer, Jaap, Di Marzo, Vincenzo, Overkleeft, Herman S., van der Stelt, Mario
• Format: Article
• Language: English
• Subjects: activity-based probe; Animals; Arachidonic Acids - metabolism; Binding Sites; Brain - enzymology; Brain - metabolism; Cell Membrane - metabolism; drug discovery; endocannabinoid; Endocannabinoids - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Glycerides - metabolism; HEK293 Cells; Humans; hydrolases; Lipoprotein Lipase - antagonists & inhibitors; Lipoprotein Lipase - genetics; Lipoprotein Lipase - metabolism; Mice; Protein Binding; Protein Structure, Tertiary; Proteome; proteomics; Structure-Activity Relationship
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201306295

A model method: A strategy that combines a knowledge‐based in silico design approach and the development of novel activity‐based probes (ABPs) for the detection of endogenous diacylglycerol lipase‐α (DAGL‐α) is presented. This approach resulted in the rapid identification of new DAGL‐α inhibitors with high selectivity in the brain proteome. ABPP=activity‐based protein profiling.