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.
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