Interactions of small molecule inhibitors with secreted phospholipase A2: A review of the structural data

Abstract

The secreted phospholipase A2 (sPLA2) family of enzymes hydrolyzes glycerophospholipid substrates at the sn-2 position of the acyl ester bond. Besides their roles in the degradation of phospholipids, these enzymes also play an important role in the immune response by promoting inflammation. The products of sPLA2-catalysis (lysophospholipids and free fatty acids such as arachidonic acid) as well as secondary metabolites produced by the arachidonic acid cascade are mediators of inflammation and subsequent tissue injury. Based on their physiological functions, the sPLA2 enzymes are pharmacological targets for the treatment of diseases with an inflammatory component such as atherosclerosis and rheumatoid arthritis. Interestingly, sPLA2s may also have roles in various types of cancer such as malignant prostate cancer. While a number of sPLA2 inhibitors have been described, compounds which have been co-crystallized with human sPLA2 enzymes are of much importance as such three-dimensional structures provide valuable information regarding the structural requirements of good potency inhibitors as well as the molecular interactions between the enzyme and inhibitor. This review selected four structures of human sPLA2s complexed with inhibitors from the Protein Data Bank to illustrate the important molecular interactions of inhibitor compounds with the enzymes and to highlight the structural features important for interaction with the sPLA2 active site. In addition, the complex of the sPLA2 inhibitor, varespladib, with a Lys49-PLA2-like snake venom toxin is also discussed. Knowledge of the molecular interactions acquired from such structures would greatly aid the discovery of small molecule inhibitors of sPLA2s for the treatment of snakebite envenoming. The three-dimensional structures presented in this review have been published by various research groups and have been deposited in the Protein Data Bank.