Olla Stefania, Manetti Fabrizio, Crespan Emmanuele, Maga Giovanni, Angelucci Adriano, Schenone Silvia, Bologna Mauro, Botta Maurizio
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
Bioorg Med Chem Lett. 2009 Mar 1;19(5):1512-6. doi: 10.1016/j.bmcl.2009.01.005. Epub 2009 Jan 9.
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.
Pim1属于丝氨酸/苏氨酸激酶家族，参与细胞生长、分化和凋亡的调控。Pim1在细胞因子信号传导中起关键作用，并与大量肿瘤的发生有关，是抗癌治疗中一个非常有吸引力的靶点。在这项工作中，我们应用了一种虚拟筛选方案，旨在鉴定能够抑制Pim1活性的小分子。通过基于结构的分子建模方法寻找新型抑制剂，利用与Pim1结合的抑制剂的三维晶体结构。从蛋白质-配体复合物的知识出发，使用LigandScout软件生成药效团模型，进而用作查询来对数据库进行虚拟筛选，随后进行对接实验。结果，确定了一组用于生物学测试的受限候选物。最后，在被选为Pim1潜在抑制剂的六种化合物中，出现了两种对Pim1具有显著活性的候选物。有趣的是，这些化合物中的一种具有与先前鉴定的抑制剂不同的化学支架。
