Citation: Liu Jingtao, Ji Wentao, Wang Binghua. 3D-QSAR, Pharmacophore Model Study and Molecular Design of 6-Azaindazole Pim-1 Kinase Inhibitors[J]. Chemistry, ;2020, 83(12): 1138-1148. shu

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

1.
Department of Science, Hetao College, Inner Mongolia, Bayan Nur, 015000
2.
School of Pharmacy, Yantai University, Shandong Yantai, 264005

Corresponding author: Liu Jingtao, ljt1963@sohu.com
Received Date: 11 June 2020
Accepted Date: 14 July 2020

Figures(7)

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.
- 6-Azaindazole ring,
- Pim-1 kinase inhibitor,
- 3D-QSAR,
- Pharmacophore model,
- Surflex-dock
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1.
沈阳化工大学材料科学与工程学院沈阳 110142