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 X_I(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.