Field and Gaussian-based 3D-QSAR models on 8-amino-imidazo [1, 5a] pyrazine derivatives as Bruton’s tyrosine kinase inhibitors

Seethalakshmi Sakthivel; Julie Rebecca Joseph Mathari; Mursaleen Baba; Habeeb Shaik Mohideen

doi:10.7324/JAPS.2025.176784

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Abstract

Bruton’s tyrosine kinase (BTK) stands as a crucial enzyme implicated in various health disorders associated with B-cells, garnering significant attention over time. It presents a compelling molecular target for addressing autoimmune diseases and malignancies linked to B-cells. The inhibition of BTK has demonstrated efficacy in treating autoimmune diseases, B-cell leukemia, and lymphomas. In this study, we conducted a 3D-QSAR analysis on a series of derivatives of 8-Amino-imidazo [1, 5a] pyrazines and optimized CGI-1746 derivatives to pinpoint essential descriptors that augment their biological activity. Our study involved the creation of Gaussian and field-based 3D-QSAR models using target-based alignment derived from docked poses. These models exhibited statistical validity, with a predictive correlation coefficient (q2) of 0.67 for the Gaussian model and 0.60 for the field-based model. Additionally, conventional correlation coefficients (r2) were 0.93 and 0.92 for the Gaussian and field-based models, respectively. Contour map analyses unveiled the significance of steric and hydrophobic interactions as substantial contributing factors to the enhanced activity of these compounds. These discoveries hold significant promise for advancing research and development in the realm of BTK inhibitors.

Keyword: Autoimmune diseases pyrazine derivatives structural bioinformatics 3D-QSAR

Citation:

Sakthivel S, Mathari JRJ, Baba M, Mohideen HS. Field and Gaussian-based 3D-QSAR models on 8-amino-imidazo [1, 5a] pyrazine derivatives as Bruton’s tyrosine kinase inhibitors. J Appl Pharm Sci. 2025. Article in Press. https://doi.org/10.7324/JAPS.2025.176784

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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3. Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol. 1994;152:557-65. https://doi.org/10.4049/jimmunol.152.2.557
4. Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S, et al. Expression of Bruton's tyrosine kinase protein within the B cell lineage. Eur J Immunol. 1994;24:3100-5. https://doi.org/10.1002/eji.1830241228
5. Mohamed AJ, Yu L, Bäckesjö CM, Vargas L, Faryal R, Aints A, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009;228:58-73. https://doi.org/10.1111/j.1600-065X.2008.00741.x
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7. Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, et al. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton′ s tyrosine kinase (BTK), LFM-A13 [α-cyano-β- hydroxy-β-methyl-N-(2, 5-dibromophenyl) propenamide]. J Biol Chem. 1999;274:9587-99. https://doi.org/10.1074/jbc.274.14.9587
8. Mao C, Zhou M, Uckun FM. Crystal structure of Bruton's tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-linked agammaglobulinemia. J Biol Chem. 2001;276:41435-43. https://doi.org/10.1074/jbc.M104828200
9. Petro JB, Rahman SJ, Ballard DW, Khan WN. Bruton's tyrosine kinase is required for activation of IκB kinase and nuclear factor κB in response to B cell receptor engagement. J Exp Med. 2000;191:1745- 54. https://doi.org/10.1084/jem.191.10.1745
10. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood J Am Soc Hematol. 2012;119:1182-9. https://doi.org/10.1182/blood-2011-10-386417
11. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287- 96. https://doi.org/10.1182/blood-2011-01-328484
12. Tsukada S, Witte ON. X-linked agammaglobulinemia and Bruton's tyrosine kinase. Adv Exp Med Biol. 1994;365:233-8. https://doi.org/10.1007/978-1-4899-0987-9_24
13. Sakthivel S, Habeeb SK. Combined pharmacophore, virtual screening and molecular dynamics studies to identify Bruton's tyrosine kinase inhibitors. J Biomol Struct Dyn. 2018;36:4320-37. https://doi.org/10.1080/07391102.2017.1415821
14. Ghodsi R, Hemmateenejad B. QSAR study of diarylalkylimidazole and diarylalkyltriazole aromatase inhibitors. Med Chem Res. 2016;25:834-42. https://doi.org/10.1007/s00044-016-1530-1
15. Ali A, Ali A, Ahsan MJ. Discovery of structural prospects of Imidazo [1, 5-a] pyrazine derivatives as BTK inhibitors against cancer: a computational study. Lett Drug Des Discov. 2021;18:1165-77. https://doi.org/10.2174/1570180818666210802104517
16. Aparna V, Jeevan J, Ravi M, Desiraju GR, Gopalakrishnan B. 3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods. Bioorg Med Chem Lett. 2006;16:1014-20. https://doi.org/10.1016/j.bmcl.2005.10.086
17. Ahmadi S, Lotfi S, Afshari S, Kumar P, Ghasemi E. CORAL: Monte Carlo based global QSAR modelling of Bruton tyrosine kinase inhibitors using hybrid descriptors. SAR QSAR Environ Res. 2021;32:1013-31. https://doi.org/10.1080/1062936X.2021.2003429
18. Liu J, Guiadeen D, Krikorian A, Gao X, Wang J, Boga SB, et al. Discovery of 8-amino-imidazo [1, 5-a] pyrazines as reversible BTK inhibitors for the treatment of rheumatoid arthritis. ACS Med Chem Lett. 2016;7:198-203. https://doi.org/10.1021/acsmedchemlett.5b00463
19. Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, et al. Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: pyridazinone analogs with improved metabolic stability. Bioorg Med Chem Lett. 2016;26:575-9. https://doi.org/10.1016/j.bmcl.2015.11.076
20. Selvaraj C, Tripathi SK, Reddy KK, Singh SK. Tool development for Prediction of pIC50 values from the IC50 values-A pIC50 value calculator. Curr Trend Biotechnol Pharm. 2011;5:1104-9.
21. Elyashberg M, Williams A. ACD/Structure elucidator: 20 years in the history of development. Molecules. 2021;26:6623. https://doi.org/10.3390/molecules26216623
22. Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc. 1996;118:11225- 36. https://doi.org/10.1021/ja9621760
23. Kalva S, Vinod D, Saleena LM. Field-and Gaussian-based 3D-QSAR studies on barbiturate analogs as MMP-9 inhibitors. Med Chem Res. 2013;22(11):5303-13. https://doi.org/10.1007/s00044-013-0479-6
24. Laskowski RA. PDBsum: summaries and analyses of PDB structures. Nuc Acid Res. 2001;29:221-2. https://doi.org/10.1093/nar/29.1.221
25. Myint KZ, Xie XQ. Recent advances in fragment-based QSAR and multi-dimensional QSAR methods. Int J Mol Sci. 2010;11:3846-66. https://doi.org/10.3390/ijms11103846
26. Verma J, Khedkar VM, Coutinho EC. 3D-QSAR in drug design-a review. Curr Top Med Chem. 2010;10:95-115. https://doi.org/10.2174/156802610790232260

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1. Smith CE, Islam TC, Mattsson PT, Mohamed AJ, Nore BF, Vihinen M. The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. Bioessays. 2001;23:436-46. https://doi.org/10.1002/bies.1062

2. Gomez-Rodriguez J, Readinger JA, Viorritto IC, Mueller KL, Houghtling RA, Schwartzberg PL. Tec kinases, actin, and cell adhesion. Immunol Rev. 2007;218:45-64. https://doi.org/10.1111/j.1600-065X.2007.00534.x

3. Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol. 1994;152:557-65. https://doi.org/10.4049/jimmunol.152.2.557

4. Genevier HC, Hinshelwood S, Gaspar HB, Rigley KP, Brown D, Saeland S, et al. Expression of Bruton's tyrosine kinase protein within the B cell lineage. Eur J Immunol. 1994;24:3100-5. https://doi.org/10.1002/eji.1830241228

5. Mohamed AJ, Yu L, Bäckesjö CM, Vargas L, Faryal R, Aints A, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009;228:58-73. https://doi.org/10.1111/j.1600-065X.2008.00741.x

6. Kurosaki T. Molecular mechanisms in B cell antigen receptor signaling. Curr Opin Immunol. 1997;9:309-18. https://doi.org/10.1016/S0952-7915(97)80075-1

7. Mahajan S, Ghosh S, Sudbeck EA, Zheng Y, Downs S, Hupke M, et al. Rational design and synthesis of a novel anti-leukemic agent targeting Bruton′ s tyrosine kinase (BTK), LFM-A13 [α-cyano-β- hydroxy-β-methyl-N-(2, 5-dibromophenyl) propenamide]. J Biol Chem. 1999;274:9587-99. https://doi.org/10.1074/jbc.274.14.9587

8. Mao C, Zhou M, Uckun FM. Crystal structure of Bruton's tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-linked agammaglobulinemia. J Biol Chem. 2001;276:41435-43. https://doi.org/10.1074/jbc.M104828200

9. Petro JB, Rahman SJ, Ballard DW, Khan WN. Bruton's tyrosine kinase is required for activation of IκB kinase and nuclear factor κB in response to B cell receptor engagement. J Exp Med. 2000;191:1745- 54. https://doi.org/10.1084/jem.191.10.1745

10. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood J Am Soc Hematol. 2012;119:1182-9. https://doi.org/10.1182/blood-2011-10-386417

11. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117:6287- 96. https://doi.org/10.1182/blood-2011-01-328484

12. Tsukada S, Witte ON. X-linked agammaglobulinemia and Bruton's tyrosine kinase. Adv Exp Med Biol. 1994;365:233-8. https://doi.org/10.1007/978-1-4899-0987-9_24

13. Sakthivel S, Habeeb SK. Combined pharmacophore, virtual screening and molecular dynamics studies to identify Bruton's tyrosine kinase inhibitors. J Biomol Struct Dyn. 2018;36:4320-37. https://doi.org/10.1080/07391102.2017.1415821

14. Ghodsi R, Hemmateenejad B. QSAR study of diarylalkylimidazole and diarylalkyltriazole aromatase inhibitors. Med Chem Res. 2016;25:834-42. https://doi.org/10.1007/s00044-016-1530-1

15. Ali A, Ali A, Ahsan MJ. Discovery of structural prospects of Imidazo [1, 5-a] pyrazine derivatives as BTK inhibitors against cancer: a computational study. Lett Drug Des Discov. 2021;18:1165-77. https://doi.org/10.2174/1570180818666210802104517

16. Aparna V, Jeevan J, Ravi M, Desiraju GR, Gopalakrishnan B. 3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods. Bioorg Med Chem Lett. 2006;16:1014-20. https://doi.org/10.1016/j.bmcl.2005.10.086

17. Ahmadi S, Lotfi S, Afshari S, Kumar P, Ghasemi E. CORAL: Monte Carlo based global QSAR modelling of Bruton tyrosine kinase inhibitors using hybrid descriptors. SAR QSAR Environ Res. 2021;32:1013-31. https://doi.org/10.1080/1062936X.2021.2003429

18. Liu J, Guiadeen D, Krikorian A, Gao X, Wang J, Boga SB, et al. Discovery of 8-amino-imidazo [1, 5-a] pyrazines as reversible BTK inhibitors for the treatment of rheumatoid arthritis. ACS Med Chem Lett. 2016;7:198-203. https://doi.org/10.1021/acsmedchemlett.5b00463

19. Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, et al. Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: pyridazinone analogs with improved metabolic stability. Bioorg Med Chem Lett. 2016;26:575-9. https://doi.org/10.1016/j.bmcl.2015.11.076

20. Selvaraj C, Tripathi SK, Reddy KK, Singh SK. Tool development for Prediction of pIC50 values from the IC50 values-A pIC50 value calculator. Curr Trend Biotechnol Pharm. 2011;5:1104-9.

21. Elyashberg M, Williams A. ACD/Structure elucidator: 20 years in the history of development. Molecules. 2021;26:6623. https://doi.org/10.3390/molecules26216623

22. Jorgensen WL, Maxwell DS, Tirado-Rives J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc. 1996;118:11225- 36. https://doi.org/10.1021/ja9621760

23. Kalva S, Vinod D, Saleena LM. Field-and Gaussian-based 3D-QSAR studies on barbiturate analogs as MMP-9 inhibitors. Med Chem Res. 2013;22(11):5303-13. https://doi.org/10.1007/s00044-013-0479-6

24. Laskowski RA. PDBsum: summaries and analyses of PDB structures. Nuc Acid Res. 2001;29:221-2. https://doi.org/10.1093/nar/29.1.221

25. Myint KZ, Xie XQ. Recent advances in fragment-based QSAR and multi-dimensional QSAR methods. Int J Mol Sci. 2010;11:3846-66. https://doi.org/10.3390/ijms11103846

26. Verma J, Khedkar VM, Coutinho EC. 3D-QSAR in drug design-a review. Curr Top Med Chem. 2010;10:95-115. https://doi.org/10.2174/156802610790232260