Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocket
Structure-based design of novel human Pin1 inhibitors (III): Optimizing affinity beyond the phosphate recognition pocket
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DOI：
10.1016/j.bmcl.2014.07.044
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发表时间：
2014-09-01
影响因子：
2.7
通讯作者：
Murray, Brion W.
中科院分区：
文献类型：
--
作者：
Guo, Chuangxing;Hou, Xinjun;Murray, Brion W.
有效的Pin1抑制剂的设计一直是具有挑战性的，因为它的活性部位专门识别磷酸蛋白表位。先前已经报道了以磷酸为基础的Pin1抑制剂的从头设计，重点是磷酸识别口袋和成功地用羧酸盐取代磷酸基团。现在，通过对Pro结合部位的配体-蛋白质相互作用进行基于结构的优化，进一步提高了羧酸盐系列的效力，这利用了Pin1催化功能所需的氢键相互作用。使用聚焦文库方法的进一步优化导致了低纳摩尔非磷酸盐小分子Pin1抑制剂的发现。旨在改善细胞通透性的结构修饰导致了具有低微摩尔抗癌细胞增殖活性的Pin1抑制剂。(C)2014爱思唯尔有限公司。保留所有权利。
The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells. (C) 2014 Elsevier Ltd. All rights reserved.