Design and synthesis of conformationally restricted phospholipids as phospholipase A2 inhibitors.
The use of conformationally restricted phospholipids 1 and 2 has been employed to understand the conformational preference of phospholipase A2 (PLA2) for substrate phospholipids. Inhibition of porcine pancreatic PLA2 with 1 and 2 indicated a two- to fivefold preference for the distal isomer 2 over the proximal isomer 1. Based upon these studies, both side-chains of the substrate phospholipid appear to occupy the lipid binding domains near the active site with the side-chains further apart most preferred by PLA2.
Central Research and Development Department, E.I. du Pont de Nemours & Co., Wilmington, Delaware 19880.
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Magolda
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Galbraith
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003198:Computer Simulation; D015195:Drug Design; D008968:Molecular Conformation; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010743:Phospholipids / Q000138:chemical synthesis* / Q000494:pharmacology; D013379:Substrate Specificity; D013552:Swine
D010743:Phospholipids; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2