Structure-based design of novel human Pin1 inhibitors (II)
Structure-based design of novel human Pin1 inhibitors (II)
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DOI：
10.1016/j.bmcl.2010.02.033
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发表时间：
2010-04-01
影响因子：
2.7
通讯作者：
Murray, Brion W.
中科院分区：
文献类型：
--
作者：
Dong, Liming;Marakovits, Joseph;Murray, Brion W.
在发现一系列新的含磷酸盐的小分子Pin 1抑制剂之后，药物设计策略转向用具有潜在更好药物特性的电子等排体取代磷酸盐基团。羧酸类似物的效力的最初损失可能是由于假定的磷酸盐结合口袋中的电荷-电荷相互作用较弱，随后通过基于结构的脯氨酸结合位点中的配体-蛋白质相互作用的优化来恢复，从而发现亚微摩尔非磷酸盐小分子Pin 1抑制剂。(C)2010爱思唯尔有限公司版权所有。
Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge-charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand-protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor. (C) 2010 Elsevier Ltd. All rights reserved.