Ripka W C, Sipio W J, Galbraith W G
Medical Products Department, E.I. DuPont De Nemours and Co., Wilmington, Delaware 19898.
J Cell Biochem. 1989 Jul;40(3):279-86. doi: 10.1002/jcb.240400304.
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.
牛和猪胰腺磷脂酶A2的X射线结构已与交互式计算机图形技术一起用于设计针对这些酶活性位点的构象刚性新型化合物（1-间羟基苄基-2-取代苊）。体外测试证实，所设计的化合物是猪胰腺磷脂酶A2的有效抑制剂，并表现出与所提出的结合模式一致的立体选择性和构效关系。这些化合物利用了位于Leu-2和Tyr-69残基之间的疏水“凹槽”，同时将氢键功能定位在His-48的nd1-N上。实验证据表明对这种氢键受体存在区域选择性偏好。该策略的第二部分使用连接的胺取代必需的钙，从而提供双底物类似物。
