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
1. [1]
2. [2]
3. [3]
  Tarrant M K, Cole P A. Annu. Rev. Biochem., 2009, 78(01): 797~825.
4. [4]
5. [5]
6. [6]
7. [7]
  Narlik-grassow M, Blanco-aparicio C, Carnero A. Med. Res. Rev., 2014, 34(1): 136~159.
8. [8]
9. [9]
  Santio N M, Salmela M, Arola H, et al. Exp. Cell. Res., 2016, 342(02): 113~124.
10. [10]
  Xie Y, Burcu M, Linn D E, et al. Mol. Pharmacol., 2010, 78(02): 310~318.
11. [11]
  Larid P W, Vanderlugt N M T, Clarke A, et al. Nucl. Acids Res., 1993, 21(20): 4750~4755.
12. [12]
  Foulks J M, Carpenter K J, Luo B, et al. Neoplasia, 2014, 16(05): 403~412.
13. [13]
  Lin Y W, Beharry Z M, Hill E G, et al. Blood, 2010, 115(04): 824~833.
14. [14]
  Chao S W, Su M Y, Chiou L C, et al. J. Nat. Prod., 2015, 78(08): 1969~1976.
15. [15]
  Hu H, Wang X, Chan G K Y, et al. Bioorg. Med. Chem. Lett., 2015, 25(22): 5258~5264.
16. [16]
  Yu S, Yuan J, Shi J, et al. Chemom. Intell. Lab. Syst., 2015, 146: 34~41.
17. [17]
  Wang X, Magnuson S, Pastor R, et al. Bioorg. Med. Chem. Lett., 2013, 23(11): 3149~3153.
18. [18]
  Wang X, Kolesnikov A, Tay S, et al. J. Med. Chem., 2017, 60(10): 4458~4473.
19. [19]
  The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC.
20. [20]
  Niu B, Lu Y, Wang J Y, et al. Comput. Struct. Biotechnol. J., 2019, 17: 36~48.
21. [21]
  Golbraikh A, Tropsha A. J. Mo. Graphics. Modell., 2002, 20(4): 269~276.
22. [22]
  Chirico N, Gramatica P. J. Chem. Inf. Model., 2011, 51(9): 2320~2335.
23. [23]
  Ishchenko A, Zhang L, LeBrazidec J Y, et al. Bioorg. Med. Chem. Lett., 2015, 25(3): 474~480.
1. [1]
  Zhi Zhou , Yu-E Lian , Yuqing Li , Hui Gao , Wei Yi . New Insights into the Molecular Mechanism Behind Clinical Tragedies of “Cephalosporin with Alcohol”. University Chemistry, 2025, 40(3): 42-51. doi: 10.12461/PKU.DXHX202403104
2. [2]
  Xue-Peng Zhang , Yuchi Long , Yushu Pan , Jiding Wang , Baoyu Bai , Rui Ding . 定量构效关系方法学习探索：以钴卟啉活化氧气为例. University Chemistry, 2025, 40(8): 345-359. doi: 10.12461/PKU.DXHX202410107
3. [3]
  Mi Wen , Baoshuo Jia , Yongqi Chai , Tong Wang , Jianbo Liu , Hailong Wu . Improvement of Fluorescence Quantitative Analysis Experiment: Simultaneous Determination of Rhodamine 6G and Rhodamine 123 in Food Using Chemometrics-Assisted Three-Dimensional Fluorescence Method. University Chemistry, 2025, 40(4): 390-398. doi: 10.12461/PKU.DXHX202405147
4. [4]
  Yihui Song , Shangshang Qin , Kai Wu , Chengyun Jin , Bin Yu . 生物化学在高水平创新型药学人才培养中的交叉融合应用——以去甲基化酶LSD1抑制剂的活性评价为例. University Chemistry, 2025, 40(6): 341-352. doi: 10.12461/PKU.DXHX202406018
5. [5]
  Shunü Peng , Huamin Li , Zhaobin Chen , Yiru Wang . Simultaneous Application of Multiple Quantitative Analysis Methods in Gas Chromatography for the Determination of Active Ingredients in Traditional Chinese Medicine Preparations. University Chemistry, 2025, 40(10): 243-249. doi: 10.12461/PKU.DXHX202412043
6. [6]
  Shule Liu . Application of SPC/E Water Model in Molecular Dynamics Teaching Experiments. University Chemistry, 2024, 39(4): 338-342. doi: 10.3866/PKU.DXHX202310029
7. [7]
  Zhiwen HUANG , Qi LIU , Jianping LANG . W/Cu/S cluster-based supramolecular macrocycles and their third-order nonlinear optical responses. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 79-87. doi: 10.11862/CJIC.20240184
8. [8]
  Chi Li , Jichao Wan , Qiyu Long , Hui Lv , Ying Xiong . N-Heterocyclic Carbene (NHC)-Catalyzed Amidation of Aldehydes with Nitroso Compounds. University Chemistry, 2024, 39(5): 388-395. doi: 10.3866/PKU.DXHX202312016
9. [9]
  Ruiqing LIU , Wenxiu LIU , Kun XIE , Yiran LIU , Hui CHENG , Xiaoyu WANG , Chenxu TIAN , Xiujing LIN , Xiaomiao FENG . Three-dimensional porous titanium nitride as a highly efficient sulfur host. Chinese Journal of Inorganic Chemistry, 2024, 40(5): 867-876. doi: 10.11862/CJIC.20230441
10. [10]
  Zhuo WANG , Xiaotong LI , Zhipeng HU , Junqiao PAN . Three-dimensional porous carbon decorated with nano bismuth particles: Preparation and sodium storage properties. Chinese Journal of Inorganic Chemistry, 2025, 41(2): 267-274. doi: 10.11862/CJIC.20240223
11. [11]
  Yujie WANG , Laobang WANG , Zheng ZHANG , Qi LIU , Jianping LANG . Construction of W/Cu/S cluster-based supramolecular compounds via alkynyl/sulfur cycloaddition and their third-order nonlinear optical properties. Chinese Journal of Inorganic Chemistry, 2025, 41(10): 2069-2077. doi: 10.11862/CJIC.20250129
12. [12]
  Ruiying WANG , Hui WANG , Fenglan CHAI , Zhinan ZUO , Benlai WU . Three-dimensional homochiral Eu(Ⅲ) coordination polymer and its amino acid configuration recognition. Chinese Journal of Inorganic Chemistry, 2025, 41(5): 877-884. doi: 10.11862/CJIC.20250052
13. [13]
  Xichen YAO , Shuxian WANG , Yun WANG , Cheng WANG , Chuang ZHANG . Oxygen reduction performance of self?supported Fe/N/C three-dimensional aerogel catalyst layers. Chinese Journal of Inorganic Chemistry, 2025, 41(7): 1387-1396. doi: 10.11862/CJIC.20240384
14. [14]
  Rui Li , Jiayu Zhang , Anyang Li . Two Levels of Understanding of Chemical Bonds: a Case of the Bonding Model of Hypervalent Molecules. University Chemistry, 2024, 39(2): 392-398. doi: 10.3866/PKU.DXHX202308051
15. [15]
  Wenliang Wang , Weina Wang , Sufan Wang , Tian Sheng , Tao Zhou , Nan Wei . “Schrödinger Equation – Approximate Models – Core Concepts – Simple Applications”: Constructing a Logical Framework and Knowledge Graph of Atom and Molecule Structures. University Chemistry, 2024, 39(8): 338-343. doi: 10.3866/PKU.DXHX202312084
16. [16]
  Hong RAO , Yang HU , Yicong MA , Chunxin LÜ , Wei ZHONG , Lihua DU . Synthesis and in vitro anticancer activity of phenanthroline-functionalized nitrogen heterocyclic carbene homo- and heterobimetallic silver/gold complexes. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2429-2437. doi: 10.11862/CJIC.20240275
17. [17]
  Yuanyuan Ping , Wangqing Kong . 光催化碳氢键官能团化合成1-苯基-1,2-乙二醇. University Chemistry, 2025, 40(6): 238-247. doi: 10.12461/PKU.DXHX202408092
18. [18]
  Manman Jin , Zhiguo Lv , Qingtao Niu . Teaching Reformation and Case Study for “Chemical Process Development and Design” Based on “Just-in-Time” Dynamic and Accurate Matching Industrial Needs. University Chemistry, 2024, 39(11): 108-116. doi: 10.12461/PKU.DXHX202403030
19. [19]
  Xiaohang JIN , Qi LIU , Jianping LANG . Room‑temperature solid‑state synthesis, structure, and third‑order nonlinear optical properties of phosphine‑ligand‑protected silver thiolate clusters. Chinese Journal of Inorganic Chemistry, 2025, 41(8): 1505-1512. doi: 10.11862/CJIC.20250125
20. [20]
  Tianlong Zhang , Rongling Zhang , Hongsheng Tang , Yan Li , Hua Li . Online Monitoring and Mechanistic Analysis of 3,5-diamino-1,2,4-triazole (DAT) Synthesis via Raman Spectroscopy: A Recommendation for a Comprehensive Instrumental Analysis Experiment. University Chemistry, 2024, 39(6): 303-311. doi: 10.3866/PKU.DXHX202312006

Get Citation

PDF

XML

Metrics

PDF Downloads(7)
Abstract views(1043)
HTML views(251)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142