Citation: Jian-Bo TONG, Xue-Chun XIAO, Ding LUO, Hai-Yin XU, Jie WANG. QSAR Study and Molecular Design of Isoquinolone Derivative JNK1 Inhibitors[J]. Chinese Journal of Structural Chemistry, ;2021, 40(12): 1586-1594. doi: 10.14102/j.cnki.0254-5861.2011-3227 shu

QSAR Study and Molecular Design of Isoquinolone Derivative JNK1 Inhibitors

Jian-Bo TONG ^{a, b,,} ,
Xue-Chun XIAO ^{a, b} ,
Ding LUO ^{a, b} ,
Hai-Yin XU ^{a, b} ,
Jie WANG ^{a, b}

a.
College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
b.
Shaanxi Key Laboratory of Chemical Additives for Industry, Xi'an 710021, China

Corresponding author: Jian-Bo TONG, jianbotong@aliyun.com
Received Date: 21 April 2021
Accepted Date: 15 June 2021

Figures(6)

JNK1 is a drug target for the treatment of type 2 diabetes, and it plays a key mediator role in metabolic disorders. In this paper, holographic quantitative structure-activity relationship (HQSAR) technology and Topomer comparative molecular field analysis (Topomer CoMFA) technology are used to analyze the quantitative structure-activity relationship (QSAR) of 39 isoquinolone derivatives. The cross validation correlation coefficient (q²) is 0.696 (Topomer CoMFA) and 0.826 (HQSAR), and the non-cross validation correlation coefficient (r²) is 0.935 (Topomer CoMFA) and 0.987 (HQSAR). The results showed that the models have good stability and predictive ability. The Topomer search module was applied to define high contribution fragments in the ZINC database, designing 20 new isoquinolone compounds with theoretically high inhibitory activity. The molecular docking was carried out to explore the interaction between the ligand and target JNK1 protein. This study can provide a theoretical basis for the design of new JNK1 inhibitors.
- Topomer CoMFA,
- HQSAR,
- molecular docking,
- isoquinolone derivatives,
- molecular design
1. [1]
  Weston, C. R.; Davis, R. J. The JNK signal transduction pathway. Curr. Opin. Genet. Dev. 2002, 12, 14−21. doi: 10.1016/S0959-437X(01)00258-1
2. [2]
  Barr, R. K.; Bogoyevitch, M. A. The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs). Int. J. Biochem. Cell B 2001, 33, 1047−1063. doi: 10.1016/S1357-2725(01)00093-0
3. [3]
  Gupta, S.; Barrett, T.; Whitmarsh, A. J.; Cavanagh, J.; Sluss, H. K.; Dérijard, B.; Davis, R. J. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996, 15, 2760–2770. doi: 10.1002/j.1460-2075.1996.tb00636.x
4. [4]
  Hirosumi, J.; Tuncman, G.; Chang, L. F.; Görgün, C. Z.; Uysal, K. T.; Maeda, K.; Karin, M.; Hotamisligil, G. S. A central role for JNK in obesity and insulin resistance. Nature 2002, 420, 333−336. doi: 10.1038/nature01137
5. [5]
  Bennett, B. L.; Satoh, Y.; Lewis, A. J. JNK: a new therapeutic target for diabetes. Curr. Opin. Pharmacol. 2003, 3, 420−425. doi: 10.1016/S1471-4892(03)00068-7
6. [6]
  Eshak, E. S.; Isao, M.; Hironori, I.; Kazumasa, Y.; Akiko, T.; Hiroyasu, I. Manganese intake from foods and beverages is associated with a reduced risk of type 2 diabetes. Maturitas 2021, 143, 127−131. doi: 10.1016/j.maturitas.2020.10.009
7. [7]
  Abdizadeh, R.; Hadizadeh, F.; Abdizadeh, T. QSAR analysis of coumarin-based benzamides as histone deacetylase inhibitors using CoMFA, CoMSIA and HQSAR methods. J. Mol. Struct. 2020, 1199, 126961−22. doi: 10.1016/j.molstruc.2019.126961
8. [8]
  More, U. A.; Patel, S.; Rahevar, V.; Noolvi, M. N.; Aminabhavi, T. M.; Joshi, S. D. In silico ADME and QSAR studies on a set of coumarin derivatives as acetylcholinesterase inhibitors against Alzheimer's disease: CoMFA, CoMSIA, Topomer CoMFA, and HQSAR. Lett. Drug Des. Discov. 2020, 17, 684−712. doi: 10.2174/1570180816666190712095907
9. [9]
  Wang, J. L.; Chen, W. W.; Zhong, H.; Luo, Y.; Zhang, L. L.; He, L.; Wu, C. J.; Li, L. Identify of promising isoquinolone JNK1 inhibitors by combined application of 3D-QSAR, molecular docking and molecular dynamics simulation approaches. J. Mol. Struct. 2021, 1225, 127−129.
10. [10]
  Tong, J. B.; Luo, D.; Zhang, X.; Bian, S. Design of novel SHP2 inhibitors using Topomer CoMFA, HQSAR analysis, and molecular docking. Struct. Chem. 2021, 32, 1061–1076. doi: 10.1007/s11224-020-01677-8
11. [11]
  Tong, J. B.; Feng, Y.; Wang, T. H.; Wu, L. Y. Topomer CoMFA, HQSAR studies and molecular docking of 2, 5-diketopiperazine derivatives as oxytocin inhibitors. Chin. J. Struc. Chem. 2020, 39, 1385−1394.
12. [12]
  Tong, J. B.; Luo, D.; Bian, S.; Zhang, X. Structural investigation of tetrahydropteridin analogues as selective PLK1 inhibitors for treating cancer through combined QSAR techniques, molecular docking, and molecular dynamics simulations. J. Mol. Liq. 2021, 335, 116235−17. doi: 10.1016/j.molliq.2021.116235
13. [13]
  Ferri, E.; Petosa, C.; Mckenna, C. E. Bromodomains: structure, function and pharmacology of inhibition. Biochem. Pharmacol. 2016, 106, 1−18. doi: 10.1016/j.bcp.2015.12.005
14. [14]
  Tong, J. B; Wu, L. Y.; Lei, S.; Wang, T. H.; Ma, Y. M. Molecular modeling studies of 4-Hydroxyamino α-pyranone carboxamide analogues as hepatitis C virus inhibitor using 3D-QSAR and molecular docking. Chin. J. Struc. Chem. 2020, 39, 1135−1145.
15. [15]
  Hosseini, F. S.; Amanlou, M. Anti-HCV and anti-malaria agent, potential candidates to repurpose for coronavirus infection: virtual screening, molecular docking, and molecular dynamics simulation study. Life Sci. 2020, 258, 118205−35. doi: 10.1016/j.lfs.2020.118205
16. [16]
  Shrestha, R.; Fajardo, J. E.; Fiser, A. Residue-based pharmacophore approaches to study protein-protein interactions. Curr. Opin. Struc. Biol. 2021, 67, 205−211. doi: 10.1016/j.sbi.2020.12.016
17. [17]
  Singh, S.; Pandey, V. P.; Yadav, K.; Yadav, A.; Dwivedi, U. N. Natural products as anti-cancerous therapeutic molecules targeted towards topoisomerases. Curr. Protein Pept. Sc. 2020, 21, 1103−1142. doi: 10.2174/1389203721666200918152511
18. [18]
  Zhang, S. W.; Li, T.; Pang, W.; Wu, J. J.; Wu, F. L.; Liu, Y. Y.; Wu, F. H. Synthesis, biological evaluation and molecular docking studies of combretastatin A-4 phosphoramidates as novel anticancer prodrugs. Med. Chem. Res. 2020, 29, 2192–2202. doi: 10.1007/s00044-020-02632-2
19. [19]
  Chaikuad, A.; Tacconi, E. M. C.; Zimmer, J.; Liang, Y. K.; Gray, N. S.; Tarsounas, M.; Knapp, S. A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. Nat. Chem. Biol. 2014, 10, 853–860. doi: 10.1038/nchembio.1629
20. [20]
  Paweł, Ś.; Amedeo, C. Protein structure-based drug design: from docking to molecular dynamics. Curr. Opin. Struc. Biol. 2018, 48, 93–102. doi: 10.1016/j.sbi.2017.10.010
21. [21]
  Tong, J. B.; Lei, S.; Qin, S. S.; Wang, Y. QSAR studies of TIBO derivatives as HIV-1 reverse transcriptase inhibitors using HQSAR, CoMFA and CoMSIA. J. Mol. Struct. 2018, 1168, 56–64. doi: 10.1016/j.molstruc.2018.05.005
22. [22]
  Tong, J. B.; Wang, T. H.; Wu, Y. J.; Feng, Y. QSAR and Docking Studies of thiazolidine-4-carboxylic acid derivatives as neuraminidase inhibitors. Chin. J. Struc. Chem. 2020, 39, 651–661.
23. [23]
  Luo, D.; Tong, J. B.; Zhang, X.; Xiao, X. C.; Bian, S. Computational strategies towards developing novel SARS-CoV-2 Mpro inhibitors against COVID-19. J. Mol. Struct. 2022, 1247, 131378–18. doi: 10.1016/j.molstruc.2021.131378
24. [24]
  Balaramnavar, V. M.; Srivastava, R.; Varshney, S.; Rawat, A. K.; Chandasana, H.; Chhonker, Y. S.; Bhatta, R. S.; Srivastava, A. K.; Gaikwad, A. N.; Lakshmi, V.; Saxena, A. K. Synthesis, biological evaluation, and molecular docking study of some new rohitukine analogs as protein tyrosine phosphatase 1B inhibitors. Bioorg. Chem. 2021, 110, 104829–11. doi: 10.1016/j.bioorg.2021.104829
1. [1]
  Fang-Yuan Chen , Wen-Chao Geng , Kang Cai , Dong-Sheng Guo . Molecular recognition of cyclophanes in water. Chinese Chemical Letters, 2024, 35(5): 109161-. doi: 10.1016/j.cclet.2023.109161
2. [2]
  Caihong Mao , Yanfeng He , Xiaohan Wang , Yan Cai , Xiaobo Hu . Synthesis and molecular recognition characteristics of a tetrapodal benzene cage. Chinese Chemical Letters, 2024, 35(8): 109362-. doi: 10.1016/j.cclet.2023.109362
3. [3]
  Cheng-Da Zhao , Huan Yao , Shi-Yao Li , Fangfang Du , Li-Li Wang , Liu-Pan Yang . Amide naphthotubes: Biomimetic macrocycles for selective molecular recognition. Chinese Chemical Letters, 2024, 35(4): 108879-. doi: 10.1016/j.cclet.2023.108879
4. [4]
  Yanwei Duan , Qing Yang . Molecular targets and their application examples for interrupting chitin biosynthesis. Chinese Chemical Letters, 2025, 36(4): 109905-. doi: 10.1016/j.cclet.2024.109905
5. [5]
  Wenyi Mei , Lijuan Xie , Xiaodong Zhang , Cunjian Shi , Fengzhi Wang , Qiqi Fu , Zhenjiang Zhao , Honglin Li , Yufang Xu , Zhuo Chen . Design, synthesis and biological evaluation of fluorescent derivatives of ursolic acid in living cells. Chinese Chemical Letters, 2024, 35(5): 108825-. doi: 10.1016/j.cclet.2023.108825
6. [6]
  Zhimin Sun , Xin-Hui Guo , Yue Zhao , Qing-Yu Meng , Li-Juan Xing , He-Lue Sun . Dynamically switchable porphyrin-based molecular tweezer for on−off fullerene recognition. Chinese Chemical Letters, 2024, 35(6): 109162-. doi: 10.1016/j.cclet.2023.109162
7. [7]
  Li Lin , Song-Lin Tian , Zhen-Yu Hu , Yu Zhang , Li-Min Chang , Jia-Jun Wang , Wan-Qiang Liu , Qing-Shuang Wang , Fang Wang . Molecular crowding electrolytes for stabilizing Zn metal anode in rechargeable aqueous batteries. Chinese Chemical Letters, 2024, 35(7): 109802-. doi: 10.1016/j.cclet.2024.109802
8. [8]
  Minghao Hu , Tianci Xie , Yuqiang Hu , Longjie Li , Ting Wang , Tongbo Wu . Allosteric DNAzyme-based encoder for molecular information transfer. Chinese Chemical Letters, 2024, 35(7): 109232-. doi: 10.1016/j.cclet.2023.109232
9. [9]
  Chuan-Zhi Ni , Ruo-Ming Li , Fang-Qi Zhang , Qu-Ao-Wei Li , Yuan-Yuan Zhu , Jie Zeng , Shuang-Xi Gu . A chiral fluorescent probe for molecular recognition of basic amino acids in solutions and cells. Chinese Chemical Letters, 2024, 35(10): 109862-. doi: 10.1016/j.cclet.2024.109862
10. [10]
  Wei-Jia Wang , Kaihong Chen . Molecular-based porous polymers with precise sites for photoreduction of carbon dioxide. Chinese Chemical Letters, 2025, 36(1): 109998-. doi: 10.1016/j.cclet.2024.109998
11. [11]
  Dongpu Wu , Zheng Yang , Yuchen Xia , Lulu Wu , Yingxia Zhou , Caoyuan Niu , Puhui Xie , Xin Zheng , Zhanqi Cao . Surface controllable wettability using amphiphilic rotaxane molecular shuttles. Chinese Chemical Letters, 2025, 36(2): 110353-. doi: 10.1016/j.cclet.2024.110353
12. [12]
  Bingwei Wang , Yihong Ding , Xiao Tian . Benchmarking model chemistry composite calculations for vertical ionization potential of molecular systems. Chinese Chemical Letters, 2025, 36(2): 109721-. doi: 10.1016/j.cclet.2024.109721
13. [13]
  Kai Ye , Zhicheng Ye , Chuantao Wang , Zhilai Luo , Cheng Lian , Chunyan Bao . Artificial signal transduction triggered by molecular photoisomerization in lipid membranes. Chinese Chemical Letters, 2025, 36(4): 110033-. doi: 10.1016/j.cclet.2024.110033
14. [14]
  Qihan Lin , Jiabin Xing , Yue-Yang Liu , Gang Wu , Shi-Jia Liu , Hui Wang , Wei Zhou , Zhan-Ting Li , Dan-Wei Zhang . taBOX: A water-soluble tetraanionic rectangular molecular container for conjugated molecules and taste masking for berberine and palmatine. Chinese Chemical Letters, 2024, 35(5): 109119-. doi: 10.1016/j.cclet.2023.109119
15. [15]
  Zhikang Wu , Guoyong Dai , Qi Li , Zheyu Wei , Shi Ru , Jianda Li , Hongli Jia , Dejin Zang , Mirjana Čolović , Yongge Wei . POV-based molecular catalysts for highly efficient esterification of alcohols with aldehydes as acylating agents. Chinese Chemical Letters, 2024, 35(8): 109061-. doi: 10.1016/j.cclet.2023.109061
16. [16]
  Jinyan Zhang , Fen Liu , Qian Jin , Xueyi Li , Qiong Zhan , Mu Chen , Sisi Wang , Zhenlong Wu , Wencai Ye , Lei Wang . Discovery of unusual phloroglucinol–triterpenoid adducts from Leptospermum scoparium and Xanthostemon chrysanthus by building blocks-based molecular networking. Chinese Chemical Letters, 2024, 35(6): 108881-. doi: 10.1016/j.cclet.2023.108881
17. [17]
  Zixi Zou , Jingyuan Wang , Yian Sun , Qian Wang , Da-Hui Qu . Controlling molecular assembly on time scale: Time-dependent multicolor fluorescence for information encryption. Chinese Chemical Letters, 2024, 35(7): 108972-. doi: 10.1016/j.cclet.2023.108972
18. [18]
  Ruonan Guo , Heng Zhang , Changsheng Guo , Ningqing Lv , Beidou Xi , Jian Xu . Degradation of neonicotinoids with different molecular structures in heterogeneous peroxymonosulfate activation system through different oxidation pathways. Chinese Chemical Letters, 2024, 35(9): 109413-. doi: 10.1016/j.cclet.2023.109413
19. [19]
  Qinghong Pan , Huafang Zhang , Qiaoling Liu , Donghong Huang , Da-Peng Yang , Tianjia Jiang , Shuyang Sun , Xiangrong Chen . A self-powered cathodic molecular imprinting ultrasensitive photoelectrochemical tetracycline sensor via ZnO/C photoanode signal amplification. Chinese Chemical Letters, 2025, 36(1): 110169-. doi: 10.1016/j.cclet.2024.110169
20. [20]
  Huanyu Liu , Gang Yu , Ruoyao Guo , Hao Qi , Jiayin Zheng , Tong Jin , Zifeng Zhao , Zuqiang Bian , Zhiwei Liu . Direct identification of energy transfer mechanism in Ce^Ⅲ-Mn^Ⅱ system by constructing molecular heteronuclear complexes. Chinese Chemical Letters, 2025, 36(2): 110296-. doi: 10.1016/j.cclet.2024.110296

Get Citation

PDF

XML

Metrics

PDF Downloads(1)
Abstract views(336)
HTML views(2)

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