STRUCTURE-BASED DESIGN OF THE FIRST POTENT AND SELECTIVE INHIBITOR OF HUMAN NONPANCREATIC SECRETORY PHOSPHOLIPASE-A(2)
STRUCTURE-BASED DESIGN OF THE FIRST POTENT AND SELECTIVE INHIBITOR OF HUMAN NONPANCREATIC SECRETORY PHOSPHOLIPASE-A(2)
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DOI：
10.1038/nsb0695-458
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发表时间：
1995-06-01
期刊：
影响因子：
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通讯作者：
WERY, JP
中科院分区：
文献类型：
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作者：
SCHEVITZ, RW;BACH, NJ;WERY, JP
利用抑制剂与酶活性位点结合的详细结构知识，从大量人非胰腺分泌型磷脂酶 A(2) (hnps-PLA(2)) 筛选中获得的先导化合物已被开发成一种有效的抑制剂。确定了 hnps-PLA(2) 与一系列越来越有效的吲哚抑制剂复合的四种晶体结构，并将其用作理解这种结合的结构基础并为进一步开发提供有价值的见解。基于结构的药物设计的应用使得这种筛选导致的酶的结合可能提高了近三个数量级。此外，优化的结构（LY311727）在针对猪胰腺 s-PLA 进行检测时显示出 1,500 倍的选择性（2）。
A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A(2) (hnps-PLA(2)) 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-PLA(2) 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-PLA(2).