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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

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 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.[1]

References

  1. Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2. Schevitz, R.W., Bach, N.J., Carlson, D.G., Chirgadze, N.Y., Clawson, D.K., Dillard, R.D., Draheim, S.E., Hartley, L.W., Jones, N.D., Mihelich, E.D. Nat. Struct. Biol. (1995) [Pubmed]
 
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