title: Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2.
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.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Schevitz
authors.forename: N J
authors.initials: NJ
authors.lastname: Bach
authors.forename: D G
authors.initials: DG
authors.lastname: Carlson
authors.forename: N Y
authors.initials: NY
authors.lastname: Chirgadze
authors.forename: D K
authors.initials: DK
authors.lastname: Clawson
authors.forename: R D
authors.initials: RD
authors.lastname: Dillard
authors.forename: S E
authors.initials: SE
authors.lastname: Draheim
authors.forename: L W
authors.initials: LW
authors.lastname: Hartley
authors.forename: N D
authors.initials: ND
authors.lastname: Jones
authors.forename: E D
authors.initials: ED
authors.lastname: Mihelich
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001681:Biological Assay; D002118:Calcium / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D054467:Phospholipases A2; D011189:Potassium Chloride / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; C095553:LY 311727; D011189:Potassium Chloride; D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium