基于结构的人类非胰腺分泌型磷脂酶A2首个强效选择性抑制剂的设计
Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2.
作者信息
Schevitz R W, Bach N J, Carlson D G, Chirgadze N Y, Clawson D K, Dillard R D, Draheim S E, Hartley L W, Jones N D, Mihelich E D
机构信息
Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
出版信息
Nat Struct Biol. 1995 Jun;2(6):458-65. doi: 10.1038/nsb0695-458.
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.
摘要
从大规模人体非胰腺分泌型磷脂酶A2（hnps-PLA2）筛选中获得的先导化合物，利用抑制剂与酶活性位点结合的详细结构知识，已被开发成一种强效抑制剂。测定了hnps-PLA2与一系列活性逐渐增强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以及为进一步开发提供有价值见解的结构基础。基于结构的药物设计的应用使该筛选先导物与酶的结合力提高了近三个数量级。此外，优化后的结构（LY311727）在针对猪胰腺s-PLA2进行测定时显示出1500倍的选择性。
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