Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors
Indolyl-pyrrolone as a new scaffold for Pim1 inhibitors
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DOI：
10.1016/j.bmcl.2009.01.005
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发表时间：
2009-03-01
影响因子：
2.7
通讯作者：
Botta, Maurizio
中科院分区：
文献类型：
--
作者：
Olla, Stefania;Manetti, Fabrizio;Botta, Maurizio
Pim1属于丝氨酸/苏氨酸激酶家族，参与细胞生长、分化和凋亡的控制。Pim1在细胞因子信号传导中起着关键作用，与大量肿瘤的发展有关，是一个非常有吸引力的抗癌治疗靶点。在这项工作中，我们应用了一种虚拟筛选方案，旨在识别能够抑制Pim1活性的小分子。利用与Pim1结合的抑制剂的三维晶体结构的可用性，通过基于结构的分子建模方法进行了新型抑制剂的搜索。从蛋白质-配体复合物的知识出发，使用LigandScout软件生成药效模型，然后将其用作查询以执行数据库的虚拟筛选，然后进行对接实验。因此，确定了一组有限的候选生物测试。最后，在筛选出的6种Pim1潜在抑制剂中，出现了2种具有显著抗Pim1活性的候选化合物。有趣的是，其中一种化合物具有不同于先前确定的抑制剂的化学支架。2009爱思唯尔有限公司版权所有。
Pim1 belongs to a family of serine/threonine kinases, which is involved in the control of cell growth, differentiation, and apoptosis. Pim1 plays a pivotal role in cytokine signaling and is implicated in the development of a large number of tumors, representing a very attractive target for anticancer therapy. In this work, we applied a virtual screening protocol aimed at identifying small molecules able to inhibit Pim1 activity. The search of novel inhibitors was performed through a structure-based molecular modeling approach, taking advantage of the availability of the three-dimensional crystal structure of inhibitors bound to Pim1. Starting from the knowledge of protein-ligand complexes, the software LigandScout was used to generate pharmacophoric models, in turn used as queries to perform a virtual screening of databases, followed by docking experiments. As a result, a restricted set of candidates for biological testing was identified. Finally, among the six compounds selected as potential inhibitors of Pim1, two candidates endowed with a significant activity against Pim1 emerged. Interestingly, one of these compounds has a chemical scaffold different from inhibitors previously identified. (C) 2009 Elsevier Ltd. All rights reserved.