Citation: Jian-Bo TONG, Yi FENG, Tian-Hao WANG, Xing ZHANG. QSAR Study of Thieno [2, 3-d] Pyrimidine as a Promising Scaffold Using HQSAR, CoMFA and CoMSIA[J]. Chinese Journal of Structural Chemistry, ;2021, 40(5): 565-575. doi: 10.14102/j.cnki.0254–5861.2011–2960 shu

QSAR Study of Thieno [2, 3-d] Pyrimidine as a Promising Scaffold Using HQSAR, CoMFA and CoMSIA

Jian-Bo TONG ^{a, b, c,,} ,
Yi FENG ^{a, b, c} ,
Tian-Hao WANG ^{a, b, c} ,
Xing ZHANG ^{a, b, c}

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, Shaanxi University of Science and Technology, Xi'an 710021, China
c.
Key Laboratory of Chemical Additives for China National Light Industry, Shaanxi University of Science and Technology, Xi'an 710021, China

Corresponding author: Jian-Bo TONG, jianbotong@aliyun.com
Received Date: 12 August 2020
Accepted Date: 21 October 2020

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

Figures(10)

In this study, CoMFA, CoMSIA and HQSAR techniques were used to study the important characteristic activities of thieno [2, 3-d] pyrimidine derivatives for effective antitumor activity. The q² value of cross validation of CoMFA model was 0.621, and r² value of non-cross validation was 0.959. The best cross validation q² value of CoMSIA model was 0.522, while the r² value of non-cross validation was 0.961. The most effective HQSAR model was obtained by taking atoms and bonds as fragments: the q² value of cross validation is 0.535, the r² value of non-cross validation is 0.871, the standard error of prediction is 0.488, and the optimal hologram length is 199. The statistical parameters from the model show that the data fit well and have high prediction ability. In addition, molecular docking is used to study the binding requirements between ligands and receptor proteins, including several hydrogen bonds between thieno [2, 3-d] pyrimidine and active site residues. The results obtained from these QSAR modeling studies can be used to design promising anticancer drugs.
- thieno [2, 3-d] pyrimidine,
- CoMFA,
- CoMSIA,
- HQSAR,
- molecular dock
1. [1]
  Pédeboscq, S.; Gravier, D.; Casadebaig, F.; Hou, G.; Gissot, A.; Rey, C.; Ichas, F.; De, G. F.; Lartigue, L.; Pometan, J. P. Synthesis and evaluation of apoptosis induction of thienopyrimidine compounds on KRAS and BRAF mutated colorectal cancer cell lines. Bioorgan. Med. Chem. 2012, 22, 6724−6731.
2. [2]
  El-Sayed, W. A.; Ali, O. M.; Zyada, R. A. F.; Mohamed, A. A.; Abdel-Rahman, A. A. H. Synthesis and antimicrobial activity of new substituted thienopyrimidines, their tetrazolyl and sugar derivatives. Acta Pol. Pharm. 2012, 3, 439−447.
3. [3]
  El-Sherbeny, M. A.; El-Ashmawy, M. B.; El-Subbagh, H. I.; El-Emam, A. A.; Badria, F. A. Synthesis, antimicrobial and antiviral evaluation of certain thienopyrimidine derivatives. Eur. J. Med. Chem. 1995, 5, 445−449.
4. [4]
  Kotaiah, Y.; Harikrishna, N.; Nagaraju, K.; Rao, C. V. Synthesis and antioxidant activity of 1, 3, 4-oxadiazole tagged thieno[2, 3-d]pyrimidine derivatives. Eur. J. Med. Chem. 2012, 12, 340−345.
5. [5]
  Shirole, N. L.; Shirole, K. D.; Deore, R. D.; Fursule, R. A.; Talele, G. S. Synthesis, characterization and pharmacological evaluation of 2-substituted thieno[2, 3-d]pyrimidine-4(3H)-ones. Asian J. Chem. 2007, 7, 4985−4992.
6. [6]
  Perrissin, M.; Favre, M.; Cuong, L. D.; Huguet, F.; Gaultier, C.; Narcisse, G. ChemInform abstract: synthesis and pharmacological activities of some substituted thienopyrimidin-4-ones. J. Cheminformatics 1989, 13, 104−105.
7. [7]
  Bousquet, E.; Guerrera, F.; Siracusa, M. A.; Caruso, A.; Amico-Roxas, M. Synthesis and pharmacological activity of 3-substituted pyrido[3΄, 2΄: 4, 5] thieno[3, 2-d] pyrimidin-4(3H)-ones. Farmaco 1984, 2, 110−119.
8. [8]
  Ashour, H. M.; Shaaban, O. G.; Rizk, O. H.; El-Ashmawy, I. M. Synthesis and biological evaluation of thieno [2΄, 3΄: 4, 5]pyrimido[1, 2-b][1, 2, 4]triazines and thieno[2, 3-d][1, 2, 4]triazolo[1, 5-a]pyrimidines as anti-inflammatory and analgesic agents. Eur. J. Med. Chem. 2013, 62, 341−351. doi: 10.1016/j.ejmech.2012.12.003
9. [9]
  Tong, J.; Shan, L.; 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
10. [10]
  Kubinyi, H. QSAR and 3D-QSAR in drug design part 1: methodology. Drug Discov. Today 1997, 11, 457−467.
11. [11]
  Abdizadeh, T.; Ghodsi, R.; Hadizadeh, F. 3D-QSAR (CoMFA, CoMSIA) and molecular docking studies on histone deacetylase 1 selective inhibitors. Recent Pat. Anti-Canc. 2017, 4, 365−383.
12. [12]
  Verma, J.; Khedkar, V. M.; Coutinho, E. C. 3D-QSAR in drug design. Curr. Top. Med. Chem. 2010, 1, 95−115.
13. [13]
  Kellogg, G. E.; Semus, S. F.; Abraham, D. J. HINT: a new method of empirical hydrophobic field calculation for CoMFA. J. Comput. Aid. Mol. Des. 1991, 6, 545−552.
14. [14]
  Bunce, J. D.; Patterson, D. E.; Frank, I. E. Crossvalidation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies. Quant. Struct-Act Rel. 1988, 1, 18−25.
15. [15]
  Klebe, G.; Abraham, U.; Mietzner, T. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J. Med. Chem. 2002, 24, 4130−4146.
16. [16]
  Salum, L. B.; Andricopulo, A. D. Fragment-based QSAR strategies in drug design. Expert. Opin. Drug. Dis. 2010, 5, 405−412. doi: 10.1517/17460441003782277
17. [17]
  Andricopulo, A. D.; Salum, L. B. Fragment-based QSAR: perspectives in drug design. Mol. Divers. 2009, 3, 277−285.
18. [18]
  Dunn III, W. J.; Wold, S.; Edlund, U.; Hellberg, S.; Gasteiger, J. Multivariate structure-activity relationships between data from a battery of biological tests and an ensemble of structure descriptors: the PLS method. Quant. Struct-Act Rel. 1984, 4, 131−137.
19. [19]
  Ali, E. M. H.; Abdel-Maksoud, M. S.; Oh, C. H. Thieno 2, 3-d pyrimidine as a promising scaffold in medicinal chemistry: recent advances. Bioorgan. Med. Chem. 2019, 7, 1159−1194.
20. [20]
  Sheila, A.; Malcolm, A. C.; Homer, R. W.; Tad, H.; Gregory, B. S. SYBYL Line notation (SLN): a versatile language for chemical structure representation. J. Chem. Inf. Model. 1997, 1, 71−79.
21. [21]
  Tong, J. B.; Zhan, P.; Wang, X. S.; Wu, Y. J. Quionolone carboxylic acid derivatives as HIV-1 integrase inhibitors: docking-based HQSAR and topomer CoMFA analyses. J. Chemometr. 2017, 12, 2934−2947.
22. [22]
  Damre, M. V.; Gangwal, R. P.; Dhoke, G. V.; Lalit, M.; Sharma, D.; Khandelwal, K.; Sangamwar, A. T. 3D-QSAR and molecular docking studies of amino-pyrimidine derivatives as PknB inhibitors. J. Taiwan. Inst. Chem. E 2014, 2, 354−364.
23. [23]
  Wang, Z. Y.; Chang, Y. Q.; Han, Y. S.; Liu, K. J.; Hou, J. S.; Dai, C. L.; Zhai, Y. H.; Guo, J. L.; Sun, P. H.; Lin, J.; Chen, W. M. 3D-QSAR and docking studies on 1-hydroxypyridin-2-one compounds as mutant isocitrate dehydrogenase 1 inhibitors. J. Mol. Struct. 2016, 6, 335−343.
24. [24]
  Hong, H.; Fang, H.; Xie, Q.; Perkins, R.; Sheehan, D. M.; Tong, W. Comparative molecular field analysis (CoMFA) model using a large diverse set of natural, synthetic and environmental chemicals for binding to the androgen receptor. Sar Qsar Environ. Res. 2003, 6, 373−388.
25. [25]
  Ghasemi, J. B.; Shiri, F. Molecular docking and 3D-QSAR studies of falcipain inhibitors using CoMFA, CoMSIA, and open 3D-QSAR. Med. Chem. Res. 2012, 10, 2788−2806.
26. [26]
  Bhonsle, J. B.; Venugopal, D.; Huddler, D. P.; Magill, A. J.; Hicks, R. P. Application of 3D-QSAR for identification of descriptors defining bioactivity of antimicrobial peptides. J. Med. Chem. 2008, 26, 6545−6553.
27. [27]
  Doddareddy, M. R.; Lee, Y. J.; Cho, Y. S.; Choi, K. I.; Koh, H. Y.; Pae, A. N. Hologram quantitative structure activity relationship studies on 5-HT6 antagonists. Bioorgan. Med. Chem. 2004, 14, 3815−3824. doi: 10.1016/j.bmcl.2004.04.103
28. [28]
  Waller, C. L. A comparative QSAR study using CoMFA, HQSAR, and FRED/SKEYS paradigms for estrogen receptor binding affinities of structurally diverse compounds. J. Chem. Inf. Model. 2004, 2, 758−765.
29. [29]
  Patel, S.; Patel, B.; Bhatt, H. 3D-QSAR studies on 5-hydroxy-6-oxo-1, 6-dihydropyrimidine-4-carboxamide derivatives as HIV-1 integrase inhibitors. J. Taiwan. Inst. Chem. E 2016, 59, 61−68.
30. [30]
  ong, J. B.; Qin, S. S.; Jiang, G. Y. 3D-QSAR study of melittin and amoebapore analogues by CoMFA and CoMSIA methods. Chin. J. Struct. Chem. 2019, 2, 201−210.
31. [31]
  Wang, Y. J.; Zhang, G. W.; Yan, J. K.; Gong, D. M. Inhibitory effect of morin on tyrosinase: insights from spectroscopic and molecular docking studies. Food Chem. 2014, 163, 226−233.
32. [32]
  Jain, A. N. Effects of protein conformation in docking: improved pose prediction through protein pocket adaptation. J. Comput. Aid. Mol. Des. 2009, 6, 355−374.
33. [33]
  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, 1, 25−36.
1. [1]
  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
2. [2]
  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
3. [3]
  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
4. [4]
  Zhenchun Yang , Bixiao Guo , Zhenyu Hu , Kun Wang , Jiahao Cui , Lina Li , Chun Hu , Yubao Zhao . Molecular engineering towards dual surface local polarization sites on poly(heptazine imide) framework for boosting H₂O₂ photo-production. Chinese Chemical Letters, 2024, 35(8): 109251-. doi: 10.1016/j.cclet.2023.109251
5. [5]
  Haojie Duan , Hejingying Niu , Lina Gan , Xiaodi Duan , Shuo Shi , Li Li . Reinterpret the heterogeneous reaction of α-Fe₂O₃ and NO₂ with 2D-COS: The role of SDS, UV and SO₂. Chinese Chemical Letters, 2024, 35(6): 109038-. doi: 10.1016/j.cclet.2023.109038
6. [6]
  Yuan Teng , Zichun Zhou , Jinghua Chen , Siying Huang , Hongyan Chen , Daibin Kuang . Dual atom-bridge effect promoting interfacial charge transfer in 2D/2D Cs₃Bi₂Br₉/BiOBr epitaxial heterojunction for efficient photocatalysis. Chinese Chemical Letters, 2025, 36(2): 110430-. doi: 10.1016/j.cclet.2024.110430
7. [7]
  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
8. [8]
  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
9. [9]
  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
10. [10]
  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
11. [11]
  Cailiang Yue , Nan Sun , Yixing Qiu , Linlin Zhu , Zhiling Du , Fuqiang Liu . A direct Z-scheme 0D α-Fe₂O₃/TiO₂ heterojunction for enhanced photo-Fenton activity with low H₂O₂ consumption. Chinese Chemical Letters, 2024, 35(12): 109698-. doi: 10.1016/j.cclet.2024.109698
12. [12]
  Yue Li , Minghao Fan , Conghui Wang , Yanxun Li , Xiang Yu , Jun Ding , Lei Yan , Lele Qiu , Yongcai Zhang , Longlu Wang . 3D layer-by-layer amorphous MoS_x assembled from [Mo₃S₁₃]^2- clusters for efficient removal of tetracycline: Synergy of adsorption and photo-assisted PMS activation. Chinese Chemical Letters, 2024, 35(9): 109764-. doi: 10.1016/j.cclet.2024.109764
13. [13]
  Ao Sun , Zipeng Li , Shuchun Li , Xiangbao Meng , Zhongtang Li , Zhongjun Li . Stereoselective synthesis of α-3-deoxy-D-manno-oct-2-ulosonic acid (α-Kdo) derivatives using a C3-p-tolylthio-substituted Kdo fluoride donor. Chinese Chemical Letters, 2025, 36(3): 109972-. doi: 10.1016/j.cclet.2024.109972
14. [14]
  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
15. [15]
  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
16. [16]
  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
17. [17]
  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
18. [18]
  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
19. [19]
  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
20. [20]
  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

Get Citation

PDF

XML

Metrics

PDF Downloads(6)
Abstract views(319)
HTML views(3)

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