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. 1995;2(6):458–465. doi: 10.1038/nsb0695-458

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

RW Schevitz 1, NJ Bach 1, DG Carlson 1, NY Chirgadze 1, DK Clawson 1, RD Dillard 1, SE Draheim 1, LW Hartley 1, ND Jones 2, ED Mihelich 1, JL Olkowski 1, DW Snyder 1, C Sommers 3, J-P Wery 1
PMCID: PMC7097651  PMID: 7664108

Abstract

A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A2 (hnps-PLA2) 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-PLA2 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-PLA2.

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