Citation: Jian-Bo TONG, Lu-Yang WU, Shan LEI, Tian-Hao WANG, Yang-Min MA. Molecular Modeling Studies of 4-Hydroxyamino α-Pyranone Carboxamide Analogues as Hepatitis C Virus Inhibitor Using 3D-QSAR and Molecular Docking[J]. Chinese Journal of Structural Chemistry, ;2020, 39(6): 1135-1145. doi: 10.14102/j.cnki.0254-5861.2011-2539 shu

Molecular Modeling Studies of 4-Hydroxyamino α-Pyranone Carboxamide Analogues as Hepatitis C Virus Inhibitor Using 3D-QSAR and Molecular Docking

Jian-Bo TONG ^{a, b,,} ,
Lu-Yang WU ^{a, b} ,
Shan LEI ^{a, b} ,
Tian-Hao WANG ^{a, b} ,
Yang-Min MA ^{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: 19 July 2019
Accepted Date: 20 November 2019

Fund Project: the National Natural Science Foundation of China 21475081the Natural Science Foundation of Shaanxi Province 2019JM-237

Figures(7)

In this paper, 42 4-hydroxyamino α-pyranone carboxamide analogues as Hepatitis C Virus (HCV) inhibitor 3D-QSAR model was built based on Topomer CoMFA. The non-cross-validation (r²), cross-validation (q²), correlation coefficient of external validation (Q_ext²), non-cross validated standard error (SD), standard error of prediction (SD_CV) and F are 0.909, 0.615, 0.967, 0.13, 0.28 and 37.287, respectively. The obtained Topomer CoMFA model has good estimation stability and prediction capability. Topomer Search was employed as a tool for virtual screening in lead-like compounds in the ZINC database. Then, 6 R₁ groups and 4 R₂ groups with higher contribution values were employed to alternately substitute for the R₁ and R₂ of the template compound 21 with the highest bioactivity. As a result, 22 new molecules with higher activity than that of the template molecule were designed successfully. The Topomer Search technology could be effectively applied to screen and design new 4-hydroxyamino α-pyranone carboxamide analogues. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HCV active site, which revealed the likely bioactive conformations. This study showed extensive interactions between the 4-hydroxyamino α-pyranone carboxamide analogues and the active sites of HCV (residues TYR466, GLN384, TYR383 and ASP335). The design of potent new inhibitors of HCV can get useful insights from these results.
- 3D-QSAR,
- 4-hydroxyamino α-pyranone carboxamide analogues,
- topomer CoMFA,
- molecule design,
- molecular docking
1. [1]
  Choo, Q. L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989, 244, 359−362. doi: 10.1126/science.2523562
2. [2]
  Hanafiah, K. M.; Groeger, J.; Flaxman, A. D.; Wiersma, S. T. Global epidemiology of hepatitis C virus infection: New estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013, 57, 1333−1342. doi: 10.1002/hep.26141
3. [3]
  Lavanchy, D. The global burden of hepatitis C. Liver. Int. 2009, 29, 74−81.
4. [4]
  Saito, I.; Miyamura, T.; Ohbayashi, A.; Harada, H.; Katayama, T.; Kikuchi, S.; Watanabe, Y.; Koi, S.; Onji, M.; Ohta, Y. Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. P. Natl. Acad. Sci. USA. 1990, 87, 6547−6549. doi: 10.1073/pnas.87.17.6547
5. [5]
  Lu, W.; Xue, Y. Prediction of hepatitis C virus non-structural proteins 5B polymerase inhibitors using machine learning methods. Acta. Phys-Chim. Sin. 2011, 27, 1407−1416. doi: 10.3866/PKU.WHXB20110608
6. [6]
  Aronoff-Spencer, E.; Venkatesh, A. G.; Sun, A.; Brickner, H.; Looney, D.; Hall, D. A. Detection of hepatitis C core antibody by dual-affinity yeast chimera and smartphone-based electrochemical sensing. Biosens. Bioelectron. 2016, 86, 690−696. doi: 10.1016/j.bios.2016.07.023
7. [7]
  Fauvelle, C.; Lepiller, Q.; Felmlee, D. J.; Fofana, I.; Habersetzer, F.; Stoll-Keller, F.; Baumert, T. F.; Fafi-Kremer, S. Hepatitis C virus vaccines-progress and perspectives. Microb. Pathog. 2013, 58, 66−72. doi: 10.1016/j.micpath.2013.02.005
8. [8]
  Law, L. M. J.; Landi, A.; Magee, W. C.; Tyrrell, D. L.; Houghton, M. Progress towards a hepatitis C virus vaccine. Emerg. Microbes. Infec. 2013, 2, e79−6.
9. [9]
  Haudecoeur, R.; Peuchmaur, M.; Ahmed-Belkacem, A.; Pawlotsky, J. M.; Boumendjel, A. Structure-activity relationships in the development of allosteric hepatitis C virus RNA-dependent RNA polymerase inhibitors: ten years of research. Med. Res. Rev. 2013, 33, 934−984. doi: 10.1002/med.21271
10. [10]
  Summa, V.; Petrocchi, A.; Matassa, V. G.; Taliani, M.; Laufer, R.; De Francesco, R.; Altamura, S.; Pace, P. HCV NS5b RNA-dependent RNA polymerase inhibitors: from α, γ-diketoacids to 4, 5-dihydroxypyrimidine or 3-methyl-5-hydroxypyrimidinonecarboxylic acids, design and synthesis. J. Med. Chem. 2004, 47, 5336−5339. doi: 10.1021/jm0494669
11. [11]
  Chen, K. X.; Njoroge, F. G. A review of HCV protease inhibitors. Curr. Opin. Invest. Dr. 2009, 10, 821−837.
12. [12]
  Watkins, W. J.; Ray, A. S.; Chong, L. S. HCV NS5B polymerase inhibitors. Curr. Opin. Drug. Disc. 2010, 13, 441−465.
13. [13]
  Legrand-Abravanel, F.; Nicot, F.; Izopet, J. New NS5B polymerase inhibitors for hepatitis C. Expert. Opin. Inv. Drug. 2010, 19, 963−975. doi: 10.1517/13543784.2010.500285
14. [14]
  Gao, M.; Nettles, R. E.; Belema, M.; Snyder, L. B.; Nguyen, V. N.; Fridell, R. A.; Serrano-Wu, M. H.; Langley, D. R.; Sun, J. H.; O'Boyle, D. R.; Lemm, J. A.; Wang, C. F.; Knipe, J. O.; Chien, C.; Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.; Hamann, L. G. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010, 465, 96−100. doi: 10.1038/nature08960
15. [15]
  Shi, J. C.; Tu, W. T.; Luo, M.; Huang, C. S. Structural insight into the design on oleanolic acid derivatives as potent protein tyrosine phosphatase 1B inhibitors. Chin. J. Struc. Chem. 2017, 36, 1063−1076.
16. [16]
  Tong, J. B.; Wang, Y.; Lei, S.; Qin, S. S. Comprehensive 3D-QSAR and binding mode of DAPY inhibitors using R-group search and molecular docking. Chin. J. Struct. Chem. 2019, 38, 25−36.
17. [17]
  Li, W. L.; Xiao, F. Q.; Zhou, M. M.; Jiang, X. J.; Liu, J.; Si, H. Z.; Xie, M.; Ma, X. T.; Duan, Y. B.; Zhai, H. L. 3D-QSAR study and design of 4-hydroxyamino α-pyranone carboxamide analogues as potential anti-HCV agents. Chem. Phys. Lett. 2016, 661, 36−41. doi: 10.1016/j.cplett.2016.08.042
18. [18]
  Clark, M.; Iii, R. D. C.; Opdenbosch, N. V. Validation of the general purpose tripos 5.2 force field. J. Comput. Chem. 1989, 10, 982−1012. doi: 10.1002/jcc.540100804
19. [19]
  Sun J. Y.; Wang, J. C.; Mei, H. QSAR and pharmacophore studies of thiazolidine-4-carboxylic acid derivatives as novel influenza neuraminidase inhibitors using HQSAR, Topomer CoMFA and CoMSIA. Chin. . J. Struc. Chem. 2013, 32, 744−750.
20. [20]
  Tong, J. B.; Bai, M.; Zhao, X. Application of an R-group search technique in the molecular design of HIV-1 integrase inhibitors. J. SERB. CHEM. SOC. 2016, 81, 383−394. doi: 10.2298/JSC150826003T
21. [21]
  Wold, S.; Sjöström, M.; Eriksson, L. PLS-regression: a basic tool of chemometrics. Chemometr. Intell. Lab. 2001, 58, 109−130. doi: 10.1016/S0169-7439(01)00155-1
22. [22]
  Bohm, M.; St rzebecher, J.; Klebe, G. Three-dimensional quantitative structure-activity relationship analyses using comparative molecular field analysis and comparative molecular similarity indices analysis to elucidate selectivity differences of inhibitors binding to trypsin, thrombin, and factor Xa. J. Med. Chem. 1999, 42, 458−477. doi: 10.1021/jm981062r
23. [23]
  Golbraikh, A.; Shen, M.; Xiao, Z.; Xiao, Y. D.; Lee, K. H.; Tropsha, A. Rational selection of training and test sets for the development of validated QSAR models. J. Comput. Aid. Mol. Des. 2003, 17, 241−253.
24. [24]
  Tong, J. B.; Qin, S. S.; Lei, S.; Wang, Y. A 3D-QSAR study of HIV-1 integrase inhibitors using RASMS and Topomer CoMFA. Chin. J. Struc. Chem. 2019, 38, 867−881.
25. [25]
  Irwin, J. J.; Sterling, T.; Mysinger, M. M.; Bolstad, E. S.; Coleman, R. G. ZINC: A free tool to discover chemistry for biology. J. Chem. Inf. Model. 2012, 52, 1757−1768.
26. [26]
  Miao, X.; Liang, G. Z. Molecular design of PTH derivatives as tau protein inhibitors using R-Group search technology. Chem. J. Chin. . U. 2012, 33, 2263−2268.
27. [27]
  Tong, J. B.; Wang, Y.; Lei, S.; Qin S. S. 3D-QSAR and docking studies of 1, 3, 4-thiazolidinone derivatives using R-Group search and surflex-dock. Chin. J. Struc. Chem. 2019, 38, 464−475.
28. [28]
  Halder, A. K.; Amin, S. A.; Jha, T.; Gayen, S. Insight into the structural requirements of pyrimidine-based phosphodiesterase 10A (PDE10A) inhibitors by multiple validated 3D-QSAR approaches. Sar. QSAR Environ. Res. 2017, 28, 253−273.
1. [1]
  Yanye Fan , Jingjing Chen , Bichun Chen , Jinyu Bai , Bowen Yang , Feng Liang , Lijing Fang . Design, synthesis and biological evaluation of Leu₁₀-teixobactin analogues. Chinese Chemical Letters, 2025, 36(4): 110075-. doi: 10.1016/j.cclet.2024.110075
2. [2]
  Brandon Bishop , Shaofeng Huang , Hongxuan Chen , Haijia Yu , Hai Long , Jingshi Shen , Wei Zhang . Artificial transmembrane channel constructed from shape-persistent covalent organic molecular cages capable of ion and small molecule transport. Chinese Chemical Letters, 2024, 35(11): 109966-. doi: 10.1016/j.cclet.2024.109966
3. [3]
  Bairu Meng , Zongji Zhuo , Han Yu , Sining Tao , Zixuan Chen , Erik De Clercq , Christophe Pannecouque , Dongwei Kang , Peng Zhan , Xinyong Liu . Design, synthesis, and biological evaluation of benzo[4,5]thieno[2,3-d]pyrimidine derivatives as novel HIV-1 NNRTIs. Chinese Chemical Letters, 2024, 35(6): 108827-. doi: 10.1016/j.cclet.2023.108827
4. [4]
  Huanyan Liu , Jiajun Long , Hua Yu , Shichao Zhang , Wenbo Liu . Rational design of highly conductive and stable 3D flexible composite current collector for high performance lithium-ion battery electrodes. Chinese Chemical Letters, 2025, 36(3): 109712-. doi: 10.1016/j.cclet.2024.109712
5. [5]
  Kun Zhang , Ni Dan , Dan-Dan Ren , Ruo-Yu Zhang , Xiaoyan Lu , Ya-Pan Wu , Li-Lei Zhang , Hong-Ru Fu , Dong-Sheng Li . A small D-A molecule with highly heat-resisting room temperature phosphorescence for white emission and anti-counterfeiting. Chinese Journal of Structural Chemistry, 2024, 43(3): 100244-100244. doi: 10.1016/j.cjsc.2024.100244
6. [6]
  Yan Cheng , Hua-Peng Ruan , Yan Peng , Longhe Li , Zhenqiang Xie , Lang Liu , Shiyong Zhang , Hengyun Ye , Zhao-Bo Hu . Magnetic, dielectric and luminescence synergetic switchable effects in molecular material [Et₃NCH₂Cl]₂[MnBr₄]. Chinese Chemical Letters, 2024, 35(4): 108554-. doi: 10.1016/j.cclet.2023.108554
7. [7]
  Linping Li , Junhui Su , Yanping Qiu , Yangqin Gao , Ning Li , Lei Ge . Design and fabrication of ternary Au/Co3O4/ZnCdS spherical composite photocatalyst for facilitating efficient photocatalytic hydrogen production. Chinese Journal of Structural Chemistry, 2024, 43(12): 100472-100472. doi: 10.1016/j.cjsc.2024.100472
8. [8]
  Ying-Yu Zhang , Jia-Qi Luo , Yan Han , Wan-Ying Zhang , Yi Zhang , Hai-Feng Lu , Da-Wei Fu . Bistable switch molecule DPACdCl₄ showing four physical channels and high phase transition temperature. Chinese Chemical Letters, 2025, 36(1): 109530-. doi: 10.1016/j.cclet.2024.109530
9. [9]
  Yinling HOU , Jia JI , Hong YU , Xiaoyun BIAN , Xiaofen GUAN , Jing QIU , Shuyi REN , Ming FANG . A rhombic Dy₄-based complex showing remarkable single-molecule magnet behavior. Chinese Journal of Inorganic Chemistry, 2025, 41(3): 605-612. doi: 10.11862/CJIC.20240251
10. [10]
  Junjun Huang , Ran Chen , Yajian Huang , Hang Zhang , Anran Zheng , Qing Xiao , Dan Wu , Ruxia Duan , Zhi Zhou , Fei He , Wei Yi . Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α_1D/1A-adrenoceptor antagonist and homology modelling. Chinese Chemical Letters, 2024, 35(11): 109594-. doi: 10.1016/j.cclet.2024.109594
11. [11]
  Hualin Jiang , Wenxi Ye , Huitao Zhen , Xubiao Luo , Vyacheslav Fominski , Long Ye , Pinghua Chen . Novel 3D-on-2D g-C₃N₄/AgI._x._y heterojunction photocatalyst for simultaneous and stoichiometric production of H₂ and H₂O₂ from water splitting under visible light. Chinese Chemical Letters, 2025, 36(2): 109984-. doi: 10.1016/j.cclet.2024.109984
12. [12]
  Shuwen SUN , Gaofeng WANG . Design and synthesis of a Zn(Ⅱ)-based coordination polymer as a fluorescent probe for trace monitoring 2, 4, 6-trinitrophenol. Chinese Journal of Inorganic Chemistry, 2025, 41(4): 753-760. doi: 10.11862/CJIC.20240399
13. [13]
  Keke Han , Wenjun Rao , Xiuli You , Haina Zhang , Xing Ye , Zhenhong Wei , Hu Cai . Two new high-temperature molecular ferroelectrics [1,5-3.2.2-Hdabcni]X (X = ClO₄⁻, ReO₄⁻). Chinese Chemical Letters, 2024, 35(6): 108809-. doi: 10.1016/j.cclet.2023.108809
14. [14]
  Caili Yang , Tao Long , Ruotong Li , Chunyang Wu , Yuan-Li Ding . Pseudocapacitance dominated Li₃VO₄ encapsulated in N-doped graphene via 2D nanospace confined synthesis for superior lithium ion capacitors. Chinese Chemical Letters, 2025, 36(2): 109675-. doi: 10.1016/j.cclet.2024.109675
15. [15]
  Hualei Xu , Manman Han , Haiqiang Liu , Liang Qin , Lulu Chen , Hao Hu , Ran Wu , Chenyu Yang , Hua Guo , Jinrong Li , Jinxiang Fu , Qichen Hao , Yijun Zhou , Jinchao Feng , Xiaodong Wang . 4-Nitrocatechol as a novel matrix for low-molecular-weight compounds in situ detection and imaging in biological tissues by MALDI-MSI. Chinese Chemical Letters, 2024, 35(6): 109095-. doi: 10.1016/j.cclet.2023.109095
16. [16]
  Jiajun Wang , Guolin Yi , Shengling Guo , Jianing Wang , Shujuan Li , Ke Xu , Weiyi Wang , Shulai Lei . Computational design of bimetallic TM₂@g-C₉N₄ electrocatalysts for enhanced CO reduction toward C₂ products. Chinese Chemical Letters, 2024, 35(7): 109050-. doi: 10.1016/j.cclet.2023.109050
17. [17]
  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
18. [18]
  Ali Dai , Zhiguo Zheng , Liusheng Duan , Jian Wu , Weiming Tan . Small molecule chemical scaffolds in plant growth regulators for the development of agrochemicals. Chinese Chemical Letters, 2025, 36(4): 110462-. doi: 10.1016/j.cclet.2024.110462
19. [19]
  Yuexi Guo , Zhaoyang Li , Jingwei Dai . Charlie and the 3D Printing Chocolate Factory. University Chemistry, 2024, 39(9): 235-242. doi: 10.3866/PKU.DXHX202309067
20. [20]
  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

Get Citation

PDF

XML

Metrics

PDF Downloads(1)
Abstract views(282)
HTML views(5)

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