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
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