Molecular modeling in the design of phospholipase A2 inhibitors.

The X-ray structures of pancreatic bovine and porcine phospholipases A2 have been used along with interactive computer graphics to design conformationally rigid, novel compounds (1-meta-hydroxybenzyl-2-substituted acenaphthenes) directed at the active sites of these enzymes. In vitro testing confirmed that the designed compounds are potent inhibitors of the porcine pancreatic phospholipase A2 and exhibit both stereoselectivity and structure-activity relationships that are consistent with the proposed mode of binding. These compounds take advantage of a hydrophobic "slot" positioned between residues Leu-2 and Tyr-69 while positioning hydrogen-bonding functionality directed at the nd1-N of His-48. Experimental evidence shows a regioselective preference for this H-bond acceptor. A second part of the strategy used a tethered amine to displace the essential calcium providing a bisubstrate analog.