Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2

A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A 2 (hnps-PLA 2 ) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA 2 complexed with a series of increasingly potent indole inhibitors were determined and used as the structural basis for both understanding this binding and providing valuable insights for further development. The application of structure-based drug design has made possible improvements in the binding of this screening lead to the enzyme by nearly three orders of magnitude. Furthermore, the optimized structure (LY311727) displayed 1,500-fold selectivity when assayed against porcine pancreatic s-PLA 2 .