6-氮杂吲唑类Pim-1激酶抑制剂的3D-QSAR、药效团模型研究和分子设计

Pim-1 激酶通过作用于多种信号通路或靶点影响肿瘤的发生发展，近年来被认为是肿瘤治疗的良好靶标。本文采用SYBYL-X2. 1. 1软件中的TopomerCoMFA、GALAHAD模块建立计算机模型，研究39个基于6-氮杂吲唑环的Pim-1激酶抑制剂的三维定量构效关系及药效团特征元素。结果显示，TopomerCoMFA建模所得交叉验证系数（q2）和相关系数（r2）分别为0. 756和0. 951，结合外部验证表明此3D-QSAR模型具有较高预测能力及较好的统计学稳定性，同时，用等势图描述了R1、R2基团处立体场、静电场对活性的具体影响。药效团研究结果表明，含氢键受体的芳香杂环母核结构，以及侧链取代基中含有芳香杂环结构对化合物的活性贡献较大。最后根据上述模型信息新设计了15个Pim-1激酶抑制剂分子并完成活性预测及分子对接模式研究，其中4个分子的预测pIC50高于建模分子中活性最好的化合物17，Surflex-Dock分析显示新设计分子均与Pim-1激酶形成较强氢键相互作用。基于6-氮杂吲唑环的Pim-1激酶抑制剂的3D-QSAR模型以及药效团模型可用于指导新型抑制剂的结构优化，为设计和开发具有较高活性的新型Pim-1激酶抑制剂提供有效帮助。

3D-QSAR, Pharmacophore Model Study and Molecular Design of 6-Azaindazole Pim-1 Kinase Inhibitors

Pim-1 kinase has become a candidate therapeutic target of tumor, which affects tumorigenesis and progression by acting on multiple signaling pathways and targets. To provide a reference for the design of novel Pim-1 kinase inhibitor, we established computational models via Topomer CoMFA and GALAHAD modules in software SYBYL-X2.1.1, then 3D-QSAR and pharmacophore characteristic elements of 39 Pim-1 kinase inhibitors based on 6-azaindazole ring were studied. The results showed that the q2 and r2 obtained by Topomer CoMFA model were 0.756 and 0.951, respectively. Combined with external validation, it concluded that the 3D-QSAR model has good predictive ability and statistical stability. The isopotential diagram described specific effects of stereoscopic field and electrostatic field on its activity at R1, R2 group. The results of pharmacophore showed that aromatic heterocyclic structures with hydrogen bond receptors and compounds containing aromatic heterocyclic structures in side chain substituents contributed significantly to the activity of compounds. Finally, according to the above model information, 15 new Pim-1 kinase inhibitors were designed, and prediction of the activity and molecular docking mode studies were completed. The prediction pIC50 of 4 molecules was higher than that of the best compound 17. Surflex-Dock analysis showed that the newly designed molecules formed strong hydrogen bond interactions with Pim-1 kinase. The results suggested that the 3D-QSAR model and the pharmacophore model of the Pim-1 kinase inhibitors based on 6-azaindazole ring can be used to guide the structural optimization of novel inhibitor, and to provide theoretical guidance for the future design of novel Pim-1 kinase inhibitor.