In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma

Shashanka T M; Prabhudas Nelaturi

Research Article

Year 2025, Volume: 26 Issue: 2, 135 - 142, 15.10.2025

Abstract

Oral skuamöz hücreli karsinom (OSHK), tütün kullanımı, viral enfeksiyonlar ve genetik yatkınlıklar gibi risk faktörleriyle güçlü ilişkilide olan baskın bir kanser tipidir. Genetik risk faktörleri arasında genellikle çeşitli biyolojik yolaklar için kritik olan gen polimorfizmleri yer almaktadır. Glutatyon S-transferaz pi 1 (GSTP1), oral kanserojenlerin detoksifikasyonunda rol oynayan bir gendir ve GSTP1'in Ile105Val varyantı, OSHK dahil olmak üzere kanser gelişimi riskinin artmasıyla ilişkilidir. GSTP1 ile nikotin gibi kanserojenler arasındaki etkileşimin anlaşılması, OSHK ilerlemesi konusunda değerli bilgiler sunmaktadır. Bu çalışmada, nikotin ve GSTP1 arasındaki bağlanma afinitesini keşfetmek için moleküler yerleştirme tekniğiyle in silico tarama kullanılmıştır. İlaç benzerliği ve farmakokinetik değerlendirmeler için PubChem'den kanonik SMILES kullanılmıştır. ToxiM platformu aracılığıyla yapılan toksisite değerlendirmesinin yanı sıra, yerleştirme analizi -7,1 kcal/mol puanlık güçlü bir bağlanma afinitesi ortaya koymuştur. Etkileşim, 3,579 Å'da TYR109 ile bir Pi-sigma bağı ve PHE9, ARG14 ve ILE105 ile Pi-alkil bağları ile stabilize edilmiştir. Bu bulgular, GSTP1'in, özellikle Ile105Val varyantının OSHK ilerlemesindeki kritik rolünü vurgular niteliktedir. Sonuçlar, GSTP1'in kanserojen detoksifikasyonuna katılımını vurgulamış ve OSHK'nın biyokimyasal yollarının daha iyi anlaşılmasına katkıda bulunmuştur.

Project Number

References

1. Akkus, N., & Kucuk Kurtulgan, H. (2025). Glutathione S-transferase polymorphisms and their role in recurrent pregnancy loss: A genetic risk assessment. Turkish Journal of Obstetrics and Gynecology, 22(1), 19-25. https:// doi.org/10.4274/tjod.galenos.2025.57609
2. Arja, C., Ravuri, R. R., Pulamaghatta, V. N., Surapaneni, K. M., Raya, P., Adimoolam, C., & Kanala, K. R. (2014). Genetic determinants of chronic obstructive pulmonary disease in South Indian male smokers. PLoS One, 9(2), e89957. https://doi.org/10.1371/journal.pone.0089957
3. Awad, A. A., Itumalla, R., Gaidhane, A. M., Khatib, M. N., Ballal, S., Bansal, P., Srivastava, M., Arora, I., Kumar, M., Sinha, A., Pant, K., Serhan, H. A., & Shabil, M. (2024). Association of electronic cigarette use and suicidal behaviors: a systematic review and meta-analysis. BMC Psychiatry, 24(1), 608. https://doi. org/10.1186/s12888-024-06012-7
4. Barr, J., Sharma, C. S., Sarkar, S., Wise, K., Dong, L., Periyakaruppan, A., & Ramesh, G. T. (2007). Nicotine induces oxidative stress and activates nuclear transcription factor kappa B in rat mesencephalic cells. Molecular and Cellular Biochemistry, 297(1-2), 93-99. https://doi.org/10.1007/s11010-006-9333-1
5. Blaskovic, S., Donati, Y., Ruchonnet-Metrailler, I., Avila, Y., Schittny, D., Schlepütz, C. M., Schittny, J. C., & Barazzone-Argiroffo, C. (2022). Early life exposure to nicotine modifies lung gene response after elastase-induced emphysema. Respiratory Research, 23(1), 44. https://doi.org/10.1186/s12931- 022-01956-4
6. Gil, G. F., Anderson, J. A., Aravkin, A., Bhangdia, K., Carr, S., Dai, X., Flor, L. S., Hay, S. I., Malloy, M. J., McLaughlin, S. A., Mullany, E. C., Murray, C. J. L., O’Connell, E. M., Okereke, C., Sorensen, R. J. D., Whisnant, J., Zheng, P., & Gakidou, E. (2024). Health effects associated with chewing tobacco: a Burden of Proof study. Nature Communications, 15(1), 1082. https://doi.org/10.1038/ s41467-024-45074-9
7. Hollman, A. L., Tchounwou, P. B., & Huang, H.C. (2016). The Association between Gene-Environment Interactions and Diseases Involving the Human GST Superfamily with SNP Variants. International Journal of Environmental Research and Public Health, 13(4), 379. https://www.mdpi.com/1660-4601/13/4/379
8. Kaur, G., Muthumalage, T., & Rahman, I. (2018). Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products. Toxicology Letters, 288, 143-155. https://doi.org/10.1016/j. toxlet.2018.02.025
9. Kay, J., Thadhani, E., Samson, L., & Engelward, B. (2019). Inflammation-induced DNA damage, mutations and cancer. DNA Repair (Amst), 83, 102673. https://doi.org/10.1016/j.dnarep.2019.102673
10. Kheirkhah Rahimabad, P., Jones, A. D., Zhang, H., Chen, S., Jiang, Y., Ewart, S., Holloway, J. W., Arshad, H., Eslamimehr, S., Bruce, R., & Karmaus, W. (2023). Polymorphisms in Glutathione S-Transferase (GST) Genes Modify the Effect of Exposure to Maternal Smoking Metabolites in Pregnancy and Offspring DNA Methylation. Genes, 14(8), 1644. https://doi.org/10.3390/genes14081644
11. Koh, W. P., Nelson, H. H., Yuan, J. M., Van den Berg, D., Jin, A., Wang, R., & Yu, M. C. (2011). Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore. Carcinogenesis, 32(10), 1507-1511. https://doi.org/10.1093/carcin/bgr175
12. Li, W., Chen, J., & Liu, C. (2013). Glutathione S-transferase P1 Ile105Val polymorphism and oral cancer risk: a meta-analysis. International Journal of Medical Sciences, 10(4), 392-398. https://doi.org/10.7150/ijms.5770
13. Mandal, R. K., & Mittal, R. D. (2020). Glutathione S-Transferase P1 313 (A > G) Ile105Val Polymorphism Contributes to Cancer Susceptibility in Indian Population: a meta-analysis of 39 Case-Control Studies. Indian Journal of Clinical Biochemistry, 35(1), 8-19. https://doi.org/10.1007/s12291-018-0787-1
14. Marshall, S. E., Bordea, C., Haldar, N. A., Mullighan, C. G., Wojnarowska, F., Morris, P. J., & Welsh, K. I. (2000). Glutathione S-transferase polymorphisms and skin cancer after renal transplantation. Kidney International, 58(5), 2186- 2193. https://doi.org/https://doi.org/10.1111/j.1523-1755.2000.00392.x
15. Mo, Z., Pu, Y., Zhou, J., Tian, Z., Teng, J., Chen, Q., Duan, L., & Liu, R. (2021). Effect of the over-dominant expression of proteins on nicotine heterosis via proteomic analysis. Scientific Reports, 11(1), 21063. https://doi.org/10.1038/ s41598-021-00614-x
16. Pandith, A. A., Lateef, A., Shahnawaz, S., Hussain, A., Malla, T. M., Azad, N., Shehjar, F., Salim, M., & Shah, Z. A. (2013). GSTP1 gene Ile105Val polymorphism causes an elevated risk for bladder carcinogenesis in smokers. Asian Pacific Journal of Cancer Prevention, 14(11), 6375-6378. https://doi. org/10.7314/apjcp.2013.14.11.6375
17. Parl, F. F. (2005). Glutathione S-transferase genotypes and cancer risk. Cancer Letters, 221(2), 123-129. https://doi.org/https://doi.org/10.1016/j. canlet.2004.06.016
18. Ramalingam, K., Krishnan, M., Ramani, P., & Muthukrishnan, A. (2023). Quality of life assessment with european organisation for research and treatment of cancer questionnaire (head and neck module 43) and its clinicopathological correlation among patients treated for oral squamous cell carcinoma: an exploratory study. Cureus, 15(2), e34650. https://doi.org/10.7759/cureus.34650
19. Schnekenburger, M., Karius, T., & Diederich, M. (2014). Regulation of epigenetic traits of the glutathione S-transferase P1 gene: from detoxification toward cancer prevention and diagnosis. Frontiers in Pharmacology, 5, 170. https://doi. org/10.3389/fphar.2014.00170
20. Sharma, A., Pandey, A., Sharma, S., Chatterjee, I., Mehrotra, R., Sehgal, A., & Sharma, J. K. (2014). Genetic polymorphism of glutathione S-transferase P1 (GSTP1) in Delhi population and comparison with other global populations. Meta Gene, 2, 134-142. https://doi.org/10.1016/j.mgene.2013.12.003
21. Shen, Y., Huang, Q., Yuan, X., Gong, H., Xu, C., Du, H., Hsueh, C.-Y., & Zhou, L. (2024). Nicotine-induced activation of cholinergic receptor nicotinic alpha 5 subunit mediates the malignant behaviours of laryngeal squamous epithelial cells by interacting with RABL6. Cell Death Discovery, 10(1), 286. https://doi. org/10.1038/s41420-024-02051-x
22. Tan, Y., Wang, Z., Xu, M., Li, B., Huang, Z., Qin, S., Nice, E. C., Tang, J., & Huang, C. (2023). Oral squamous cell carcinomas: state of the field and emerging directions. International Journal of Oral Science, 15(1), 44. https://doi. org/10.1038/s41368-023-00249-w
23. Vasconcelos, V., & Gilbert, H. (2018). Smokers’ knowledge and perception of electronic cigarettes (e-cigarettes): a qualitative study of non-quitting smokers in a North London general practice. Primary Health Care Research & Development, 20, e38. https://doi.org/10.1017/s1463423618000439
24. Yadav, P., Banerjee, A., Boruah, N., Singh, C. S., Chatterjee, P., Mukherjee, S., Dakhar, H., Nongrum, H. B., Bhattacharjee, A., & Chatterjee, A. (2020). Glutathione S-transferasesP1 AA (105Ile) allele increases oral cancer risk, interacts strongly with c-Jun kinase and weakly detoxifies areca-nut metabolites.

In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma

Year 2025, Volume: 26 Issue: 2, 135 - 142, 15.10.2025

Shashanka T M Prabhudas Nelaturi

Abstract

Oral squamous cell carcinoma (OSCC) is a predominant cancer strongly associated with risk factors like use of tobacco, viral infections, and genetic predispositions. Genetic risk factors often involve polymorphisms in genes that are critical for various biological pathways. Glutathione S-transferase pi 1 (GSTP1) is a gene involved in detoxifying oral carcinogens and the Ile105Val variant of GSTP1 is associated with increased risk of cancer development including OSCC. Understanding the interaction between GSTP1 and carcinogens such as nicotine offers valuable insights into OSCC progression. The study employed in silico screening with molecular docking technique in order to explore the binding affinity between nicotine and GSTP1. Methods included the use of canonical SMILES from PubChem for drug-likeness and pharmacokinetic assessments. Alongside toxicity evaluation through ToxiM platform, docking analysis revealed a strong binding affinity of -7.1 kcal/mol score. The interaction was stabilized by a Pi-sigma bond with TYR109 at 3.579 Å and Pi-alkyl bonds with PHE9, ARG14, and ILE105. These findings emphasize the crucial role of GSTP1, particularly the Ile105Val variant, in progression of OSCC. The study highlighted the involvement of GSTP1 in carcinogen detoxification and contribute to a better understanding of OSCC's biochemical pathways.

Keywords

Toxicity prediction , cancer genetics , tobacco , gene-environment interactions , computational biology

Ethical Statement

Since the article does not contain any studies with human or animal subject, its approval to the ethics committee was not required.

Project Number

References

1. Akkus, N., & Kucuk Kurtulgan, H. (2025). Glutathione S-transferase polymorphisms and their role in recurrent pregnancy loss: A genetic risk assessment. Turkish Journal of Obstetrics and Gynecology, 22(1), 19-25. https:// doi.org/10.4274/tjod.galenos.2025.57609
2. Arja, C., Ravuri, R. R., Pulamaghatta, V. N., Surapaneni, K. M., Raya, P., Adimoolam, C., & Kanala, K. R. (2014). Genetic determinants of chronic obstructive pulmonary disease in South Indian male smokers. PLoS One, 9(2), e89957. https://doi.org/10.1371/journal.pone.0089957
3. Awad, A. A., Itumalla, R., Gaidhane, A. M., Khatib, M. N., Ballal, S., Bansal, P., Srivastava, M., Arora, I., Kumar, M., Sinha, A., Pant, K., Serhan, H. A., & Shabil, M. (2024). Association of electronic cigarette use and suicidal behaviors: a systematic review and meta-analysis. BMC Psychiatry, 24(1), 608. https://doi. org/10.1186/s12888-024-06012-7
4. Barr, J., Sharma, C. S., Sarkar, S., Wise, K., Dong, L., Periyakaruppan, A., & Ramesh, G. T. (2007). Nicotine induces oxidative stress and activates nuclear transcription factor kappa B in rat mesencephalic cells. Molecular and Cellular Biochemistry, 297(1-2), 93-99. https://doi.org/10.1007/s11010-006-9333-1
5. Blaskovic, S., Donati, Y., Ruchonnet-Metrailler, I., Avila, Y., Schittny, D., Schlepütz, C. M., Schittny, J. C., & Barazzone-Argiroffo, C. (2022). Early life exposure to nicotine modifies lung gene response after elastase-induced emphysema. Respiratory Research, 23(1), 44. https://doi.org/10.1186/s12931- 022-01956-4
6. Gil, G. F., Anderson, J. A., Aravkin, A., Bhangdia, K., Carr, S., Dai, X., Flor, L. S., Hay, S. I., Malloy, M. J., McLaughlin, S. A., Mullany, E. C., Murray, C. J. L., O’Connell, E. M., Okereke, C., Sorensen, R. J. D., Whisnant, J., Zheng, P., & Gakidou, E. (2024). Health effects associated with chewing tobacco: a Burden of Proof study. Nature Communications, 15(1), 1082. https://doi.org/10.1038/ s41467-024-45074-9
7. Hollman, A. L., Tchounwou, P. B., & Huang, H.C. (2016). The Association between Gene-Environment Interactions and Diseases Involving the Human GST Superfamily with SNP Variants. International Journal of Environmental Research and Public Health, 13(4), 379. https://www.mdpi.com/1660-4601/13/4/379
8. Kaur, G., Muthumalage, T., & Rahman, I. (2018). Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products. Toxicology Letters, 288, 143-155. https://doi.org/10.1016/j. toxlet.2018.02.025
9. Kay, J., Thadhani, E., Samson, L., & Engelward, B. (2019). Inflammation-induced DNA damage, mutations and cancer. DNA Repair (Amst), 83, 102673. https://doi.org/10.1016/j.dnarep.2019.102673
10. Kheirkhah Rahimabad, P., Jones, A. D., Zhang, H., Chen, S., Jiang, Y., Ewart, S., Holloway, J. W., Arshad, H., Eslamimehr, S., Bruce, R., & Karmaus, W. (2023). Polymorphisms in Glutathione S-Transferase (GST) Genes Modify the Effect of Exposure to Maternal Smoking Metabolites in Pregnancy and Offspring DNA Methylation. Genes, 14(8), 1644. https://doi.org/10.3390/genes14081644
11. Koh, W. P., Nelson, H. H., Yuan, J. M., Van den Berg, D., Jin, A., Wang, R., & Yu, M. C. (2011). Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore. Carcinogenesis, 32(10), 1507-1511. https://doi.org/10.1093/carcin/bgr175
12. Li, W., Chen, J., & Liu, C. (2013). Glutathione S-transferase P1 Ile105Val polymorphism and oral cancer risk: a meta-analysis. International Journal of Medical Sciences, 10(4), 392-398. https://doi.org/10.7150/ijms.5770
13. Mandal, R. K., & Mittal, R. D. (2020). Glutathione S-Transferase P1 313 (A > G) Ile105Val Polymorphism Contributes to Cancer Susceptibility in Indian Population: a meta-analysis of 39 Case-Control Studies. Indian Journal of Clinical Biochemistry, 35(1), 8-19. https://doi.org/10.1007/s12291-018-0787-1
14. Marshall, S. E., Bordea, C., Haldar, N. A., Mullighan, C. G., Wojnarowska, F., Morris, P. J., & Welsh, K. I. (2000). Glutathione S-transferase polymorphisms and skin cancer after renal transplantation. Kidney International, 58(5), 2186- 2193. https://doi.org/https://doi.org/10.1111/j.1523-1755.2000.00392.x
15. Mo, Z., Pu, Y., Zhou, J., Tian, Z., Teng, J., Chen, Q., Duan, L., & Liu, R. (2021). Effect of the over-dominant expression of proteins on nicotine heterosis via proteomic analysis. Scientific Reports, 11(1), 21063. https://doi.org/10.1038/ s41598-021-00614-x
16. Pandith, A. A., Lateef, A., Shahnawaz, S., Hussain, A., Malla, T. M., Azad, N., Shehjar, F., Salim, M., & Shah, Z. A. (2013). GSTP1 gene Ile105Val polymorphism causes an elevated risk for bladder carcinogenesis in smokers. Asian Pacific Journal of Cancer Prevention, 14(11), 6375-6378. https://doi. org/10.7314/apjcp.2013.14.11.6375
17. Parl, F. F. (2005). Glutathione S-transferase genotypes and cancer risk. Cancer Letters, 221(2), 123-129. https://doi.org/https://doi.org/10.1016/j. canlet.2004.06.016
18. Ramalingam, K., Krishnan, M., Ramani, P., & Muthukrishnan, A. (2023). Quality of life assessment with european organisation for research and treatment of cancer questionnaire (head and neck module 43) and its clinicopathological correlation among patients treated for oral squamous cell carcinoma: an exploratory study. Cureus, 15(2), e34650. https://doi.org/10.7759/cureus.34650
19. Schnekenburger, M., Karius, T., & Diederich, M. (2014). Regulation of epigenetic traits of the glutathione S-transferase P1 gene: from detoxification toward cancer prevention and diagnosis. Frontiers in Pharmacology, 5, 170. https://doi. org/10.3389/fphar.2014.00170
20. Sharma, A., Pandey, A., Sharma, S., Chatterjee, I., Mehrotra, R., Sehgal, A., & Sharma, J. K. (2014). Genetic polymorphism of glutathione S-transferase P1 (GSTP1) in Delhi population and comparison with other global populations. Meta Gene, 2, 134-142. https://doi.org/10.1016/j.mgene.2013.12.003
21. Shen, Y., Huang, Q., Yuan, X., Gong, H., Xu, C., Du, H., Hsueh, C.-Y., & Zhou, L. (2024). Nicotine-induced activation of cholinergic receptor nicotinic alpha 5 subunit mediates the malignant behaviours of laryngeal squamous epithelial cells by interacting with RABL6. Cell Death Discovery, 10(1), 286. https://doi. org/10.1038/s41420-024-02051-x
22. Tan, Y., Wang, Z., Xu, M., Li, B., Huang, Z., Qin, S., Nice, E. C., Tang, J., & Huang, C. (2023). Oral squamous cell carcinomas: state of the field and emerging directions. International Journal of Oral Science, 15(1), 44. https://doi. org/10.1038/s41368-023-00249-w
23. Vasconcelos, V., & Gilbert, H. (2018). Smokers’ knowledge and perception of electronic cigarettes (e-cigarettes): a qualitative study of non-quitting smokers in a North London general practice. Primary Health Care Research & Development, 20, e38. https://doi.org/10.1017/s1463423618000439
24. Yadav, P., Banerjee, A., Boruah, N., Singh, C. S., Chatterjee, P., Mukherjee, S., Dakhar, H., Nongrum, H. B., Bhattacharjee, A., & Chatterjee, A. (2020). Glutathione S-transferasesP1 AA (105Ile) allele increases oral cancer risk, interacts strongly with c-Jun kinase and weakly detoxifies areca-nut metabolites.

There are 24 citations in total.

Details

Primary Language	English
Subjects	Sequence Analysis
Journal Section	Research Article/Araştırma Makalesi
Authors	Shashanka T M This is me 0009-0003-7428-4202 Prabhudas Nelaturi 0000-0002-0390-3235
Project Number	59
Early Pub Date	July 14, 2025
Publication Date	October 15, 2025
Submission Date	January 24, 2025
Acceptance Date	June 10, 2025
Published in Issue	Year 2025 Volume: 26 Issue: 2

Cite

APA	T M, S., & Nelaturi, P. (2025). In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma. Trakya University Journal of Natural Sciences, 26(2), 135-142.
AMA	T M S, Nelaturi P. In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma. Trakya Univ J Nat Sci. October 2025;26(2):135-142.
Chicago	T M, Shashanka, and Prabhudas Nelaturi. “In Silico Analysis of Molecular Docking Between Nicotine and GSTP1 Gene in Oral Squamous Cell Carcinoma”. Trakya University Journal of Natural Sciences 26, no. 2 (October 2025): 135-42.
EndNote	T M S, Nelaturi P (October 1, 2025) In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma. Trakya University Journal of Natural Sciences 26 2 135–142.
IEEE	S. T M and P. Nelaturi, “In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma”, Trakya Univ J Nat Sci, vol. 26, no. 2, pp. 135–142, 2025.
ISNAD	T M, Shashanka - Nelaturi, Prabhudas. “In Silico Analysis of Molecular Docking Between Nicotine and GSTP1 Gene in Oral Squamous Cell Carcinoma”. Trakya University Journal of Natural Sciences 26/2 (October2025), 135-142.
JAMA	T M S, Nelaturi P. In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma. Trakya Univ J Nat Sci. 2025;26:135–142.
MLA	T M, Shashanka and Prabhudas Nelaturi. “In Silico Analysis of Molecular Docking Between Nicotine and GSTP1 Gene in Oral Squamous Cell Carcinoma”. Trakya University Journal of Natural Sciences, vol. 26, no. 2, 2025, pp. 135-42.
Vancouver	T M S, Nelaturi P. In silico analysis of molecular docking between nicotine and GSTP1 gene in oral squamous cell carcinoma. Trakya Univ J Nat Sci. 2025;26(2):135-42.

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