Lipidomics-based assays coupled with computational approaches can identify novel phospholipase A2 inhibitors.

Phospholipase A2 (PLA2) enzymes play a major role in many diseases including the inflammatory cascade and specific potent small molecule inhibitors could be useful in studying their physiological role as well as for the development of drugs. In order to discover novel small molecule inhibitor platforms for members of the PLA2 superfamily of enzymes, we have applied computational approaches to determine the binding mode of potent inhibitors specific for particular PLA2s to the screening of chemical libraries. This has including the U.S. National Institutes of Health (NIH) National Cancer Institute (NCI) Diversity Set V and the ChemBridge commercial compound libraries. We have then subjected identified inhibitor structures to recently developed lipidomics based screening assays to determine the XI(50) and specificity of the identified compounds for specific PLA2s. Herein we review this approach and report the identity of initial hits for both the Group IVA cytosolic PLA2 and the Group VIA calcium-independent PLA2 that are worthy of further structural modification to develop novel platforms for inhibitor development.

ß-Lactones: A Novel Class of Ca2+-Independent Phospholipase A2 (Group VIA iPLA2) Inhibitors with the Ability To Inhibit ß-Cell Apoptosis.

Ca2+-independent phospholipase A2 (GVIA iPLA2) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA2 inhibitors based on the ß-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA2 inhibitor ever reported ( XI(50) 0.0000021, IC50 1 nM) and also one that is 22 000 times more active against GVIA iPLA2 than GIVA cPLA2. It was found to reduce ß-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.