Exploring the Protein-Protein Interactions and the Physiological Impact of Cannabinoids through Bioinformatics Analysis

Shyam Sundar  Shaha; Akhi  Akter; Ruku  Akter; Mehadi Hasan  Evan; Mst Tasmina  Akter; Md Rifat  Ahmed; Jwel  Sharma; Mita Rani  Das; Yousuf Al  Mamun; Md  Abdullah; Md Liton  Miah; Elachi  Akter; Md Ramjan  Sheikh

doi:10.3329/brc.v11i2.82643

Authors

Shyam Sundar Shaha Department of Biochemistry & Molecular Biology, Gono Bishwabidyalay, Savar, Dhaka-1344, Bangladesh
Akhi Akter Department of Biochemistry & Molecular Biology, Gono Bishwabidyalay, Savar, Dhaka-1344, Bangladesh
Ruku Akter Department of Biochemistry & Molecular Biology, Gono Bishwabidyalay, Savar, Dhaka-1344, Bangladesh
Mehadi Hasan Evan Department of Pharmacy, Pabna University of Science and Technology, Pabna-6600, Bangladesh
Mst Tasmina Akter Department of Biochemistry & Molecular Biology, Gono Bishwabidyalay, Savar, Dhaka-1344, Bangladesh
Md Rifat Ahmed Department of Biochemistry & Molecular Biology, Gono Bishwabidyalay, Savar, Dhaka-1344, Bangladesh
Jwel Sharma Department of Chemistry, National University, Gazipur-1704, Bangladesh
Mita Rani Das Department of Biochemistry & Molecular Biology, Jahangirnagar University, Savar, Dhaka-1342, Bangladesh
Yousuf Al Mamun Department of Biochemistry & Molecular Biology, Primeasia University, Banani, Dhaka, Bangladesh
Md Abdullah Department of Pharmacy, Pabna University of Science and Technology, Pabna-6600, Bangladesh
Md Liton Miah Department of Biochemistry & Molecular Biology, Gono Bishwabidyalay, Savar, Dhaka-1344, Bangladesh
Elachi Akter Department of Textile Engineering, Southeast University, 251/A, Tejgaon Industrial Area, Dhaka – 1208, Bangladesh
Md Ramjan Sheikh Department of Biochemistry & Molecular Biology, Hajee Mohammad Danesh Science and Technology University, Dinajpur-5200, Bangladesh

DOI:

https://doi.org/10.3329/brc.v11i2.82643

Keywords:

PCI, PPI, Delta 9-tetrahydrocannabinol, Cannabidiol, Functional analysis

Abstract

Background: Weed smoking is a vastly unfavorable and perilous practice that can lead to various diseases, but it can also have beneficial effects on the human body. It comprises mainly two bioactive cannabinoids, delta 9-tetrahydrocannabinol and cannabidiol; they have both adverse and beneficial effects on human health. Objective: This study aims to identify the proteins interacting with delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) to predict their potential influences on the human body. Materials and Methods: We retrieved 200 proteins from the STITCH and STRING databases to analyze the interaction networks (PCI and PPI). We used OmicsBox to perform functional and pathway analysis of proteins associated with these compounds. Furthermore, the Cytoscape networking tool was utilized to identify crucial proteins and their significant pathways. We used Pyrx to assess potential direct interactions between THC and CBD with their associated proteins. Results: Functional annotation analysis revealed that THC and CBD interacted with various biological processes of human health, including signaling, anatomical structure development, cell differentiation, DNA binding, oxidoreductase activity, and cytosol activity. Fourteen key proteins were identified based on degree centrality, including ESR1, CREB1, INS, POMC, CNR1, JUN, NTRK2, CYP2B6, PPIG, CYP3A4, CYP1A2, CYP2E1, CYP2C9, and CYP2C19. These proteins play regulatory roles in various Reactome and KEGG pathways. Hypothetical direct interaction analysis showed that THC strongly interacted with pre-prodynorphin protein (-8.5 kcal/mol) and CBD connected with Cytochrome P450 1A1 protein (-8 kcal/mol). Conclusion: Therefore, this study contributes to understanding protein interactions and pathways, aiding in the development of drugs targeting CBD- or THC-related changes or associated diseases.

References

Abrams, D.I. (2018). "The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report", European Journal of Internal Medicine, Vol. 49, pp. 7-11.

Abyadeh, M., Gupta, V., Liu, X., Rossio, V., Mirzaei, M., Cornish, J., Paulo, J.A., and Haynes, P.A. (2023). "Proteome-wide profiling using sample multiplexing of a human cell line treated with cannabidiol (CBD) and tetrahydrocannabinol (THC)", Proteomes, Vol. 11 No. 4, pp. 36.

Amin, M.R., and Ali, D.W. (2019). "Pharmacology of Medical Cannabis", Springer International Publishing, Vol. 1162, pp. 151-165.

Anzenbacher, P., and Anzenbacherová, E. (2001). "Cytochromes P450 and metabolism of xenobiotics", Cellular and Molecular Life Sciences, Vol. 58 No. 5, pp. 737-747.

Atakan, Z. (2012). "Cannabis, a complex plant: Different compounds and different effects on individuals", Therapeutic Advances in Psychopharmacology, Vol. 2 No. (6), pp. 241-254.

Balachandran, P., Elsohly, M., and Hill, K. P. (2021). "Cannabidiol interactions with medications, illicit substances, and alcohol: A comprehensive review", Journal of General Internal Medicine, Vol. 36 No. (7), pp. 2074-2084.

Bian, Y., He, X., Jing, Y., Wang, L., Wang, J., and Xie, X.-Q. (2019). "Computational systems pharmacology analysis of cannabidiol: A combination of chemogenomics-knowledgebase network analysis and integrated in silico modeling and simulation", Acta Pharmacologica Sinica, Vol. 40 No. 3, 374-386.

Boggs, D. L., Nguyen, J. D., Morgenson, D., Taffe, M. A., and Ranganathan, M. (2018). "Clinical and preclinical evidence for functional interactions of cannabidiol and Δ9-Tetrahydrocannabinol", Neuropsychopharmacology, Vol. 43 No. 1, 142-154.

Budney, A. J., Vandrey, R. G., Hughes, J. R., Moore, B. A., and Bahrenburg, B. (2007). "Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms", Drug and Alcohol Dependence, Vol. 86 No. 1, 22-29.

Carlini, E. A. (2004). "The good and the bad effects of (−) trans-delta-9-tetrahydrocannabinol (Δ9-THC) on humans", Toxicon, Vol. 44 No. 4, 461-467.

Chetia, S., and Borah, G. (2020). "Δ 9-Tetrahydrocannabinol Toxicity and validation of cannabidiol on brain dopamine levels: An assessment on cannabis duplicity", Natural Products and Bioprospecting, Vol. 10 No. 5, 285-296.

Cohen, K., Weizman, A., and Weinstein, A. (2019). "Positive and negative effects of cannabis and cannabinoids on health", Clinical Pharmacology & Therapeutics, Vol. 105 No. 5, pp. 1139-1147.

Court, M. H., Mealey, K. L., Burke, N. S., Jimenez, T. P., Zhu, Z., and Wakshlag, J. J. (2024). "Cannabidiol and cannabidiolic acid: Preliminary in vitro evaluation of metabolism and drug–drug interactions involving canine cytochrome P‐450, UDP‐glucuronosyltransferase, and P‐glycoprotein", Journal of Veterinary Pharmacology and Therapeutics, Vol. 47 No. 1, 1-13.

Dallakyan, S., and Olson, A.J. (2015). "Small-Molecule Library Screening by Docking with PyRx", In Hempel, J.E., Williams, C. H., and Hong, C.C. (Eds.), Chemical Biology, Springer, New York, Vol. 1263, pp. 243-250.

Datta, S., Ramamurthy, P.C., Anand, U., Singh, S., Singh, A., Dhanjal, D.S., Dhaka, V., Kumar, S., Kapoor, D., Nandy, S., Kumar, M., Koshy, E.P., Dey, A., Proćków, J., and Singh, J. (2021). "Wonder or evil?: Multifaceted health hazards and health benefits of Cannabis sativa and its phytochemicals", Saudi Journal of Biological Sciences, Vol. 28 No. 12, 7290-7313.

Dhein, S. (2020). "Different effects of cannabis abuse on adolescent and adult brain", Pharmacology, Vol. 105 No. 11-12, pp. 609-617.

Hasbi, A., Madras, B.K., and George, S.R. (2023). "Daily Δ9-Tetrahydrocannabinol and withdrawal increase dopamine D1-D2 receptor heteromer to mediate anhedonia- and anxiogenic-like behavior through a dynorphin and kappa opioid receptor mechanism", Biological Psychiatry Global Open Science, Vol. 3 No. 3, pp. 550-566.

Ivanov, V.N., Wu, J., and Hei, T.K. (2017). "Regulation of human glioblastoma cell death by combined treatment of cannabidiol, γ-radiation and small molecule inhibitors of cell signaling pathways", Oncotarget, Vol. 8 No. 43, pp. 74068-74095.

James, T.R., Richards, A.A., Lowe, D.A., Reid, W.A., Watson, C.T., and Pepple, D.J. (2022). "The in vitro effect of delta-9-tetrahydrocannabinol and cannabidiol on whole blood viscosity, elasticity and membrane integrity", Journal of Cannabis Research, Vol. 4 No. 1, pp. 15.

Koneru, A., Satyanarayana, S., and Rizwan, S. (2009). "Endogenous opioids: Their physiological role and receptors", Global Journal of Pharmacology, Vol. 3 No. 3, pp. 149-153.

Kuhn, M., Szklarczyk, D., Pletscher-Frankild, S., Blicher, T.H., Von Mering, C., Jensen, L.J., and Bork, P. (2014). "STITCH 4: Integration of protein–chemical interactions with user data", Nucleic Acids Research, Vol. 42 No. D1, pp. D401-D407.

Lee, S., Lee, Y., Kim, Y., Kim, H., Rhyu, H., Yoon, K., Lee, C.D., and Lee, S. (2024). "Beneficial effects of cannabidiol from Cannabis", Applied Biological Chemistry, Vol. 67 No. 1, pp. 32.

Legare, C.A., Raup-Konsavage, W.M., and Vrana, K.E. (2022). "Therapeutic potential of cannabis, cannabidiol, and cannabinoid-based pharmaceuticals", Pharmacology, Vol. 107 No. 3-4, pp. 131-149.

Lundqvist, T. (2005). "Cognitive consequences of cannabis use: Comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions", Pharmacology Biochemistry and Behavior, Vol. 81 No. 2, pp. 319-330.

Machado, A.S., Bragança, M., and Vieira-Coelho, M. (2024). "Epigenetic effects of cannabis: A systematic scoping review of behavioral and emotional symptoms associated with cannabis use and exocannabinoid exposure", Drug and Alcohol Dependence, Vol. 263, pp. 111401.

McAllister, S.D., Murase, R., Christian, R.T., Lau, D., Zielinski, A.J., Allison, J., Almanza, C., Pakdel, A., Lee, J., Limbad, C., Liu, Y., Debs, R.J., Moore, D.H., and Desprez, P.Y. (2011). "Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis", Breast Cancer Research and Treatment, Vol. 129 No. 1, 37-47.

Miah, M.L., Hossain, M.F., Uddin, M.E., Rahman, M.H., Barua, H., Osman, A.A., Khan, M.A.A., and Sheikh, M.R. (2024). "Proteomic insights into the health impacts of cigarette smoking: analyzing nicotine, PAHs, aromatic amines, and aldehydes", Bioresearch Communications, Vol. 11 No. 1, pp. 1651-1678.

Moreno, E., Cavic, M., Krivokuca, A., and Canela, E.I. (2020). "The Interplay between cancer biology and the endocannabinoid system-significance for cancer risk, prognosis and response to treatment", Cancers, Vol. 12 No. 11, pp. 3275.

Muniyappa, R., Sable, S., Ouwerkerk, R., Mari, A., Gharib, A.M., Walter, M., Courville, A., Hall, G., Chen, K.Y., Volkow, N.D., Kunos, G., Huestis, M.A., and Skarulis, M.C. (2013a). "Metabolic effects of chronic cannabis smoking", Diabetes Care, Vol. 36 No. 8, 2415-2422.

Nilsson, S., and Gustafsson, J.A. (2002). "Biological role of estrogen and estrogen receptors", Critical Reviews in Biochemistry and Molecular Biology, Vol. 37 No. 1, pp. 1-28.

Osman, A.A., Abdi Omar, A.A., Khatun, M.A., Sheikh, M.R., Alam, M.S., Zaman, M.M.U., Abedin, M.T., and Sayed, M.A. (2023). "Biochemical analysis of Leonurus sibiricus and prediction of its bioactive compound-protein interactions in Homo sapiens", Bioresearch Communications, Vol. 10 No. 1, pp. 1398-1412.

Owen, K.P., Sutter, M.E., and Albertson, T.E. (2014). "Marijuana: Respiratory tract effects", Clinical Reviews in Allergy & Immunology, Vol. 46 No. 1, pp. 65-81.

Podinić, T., and Raha, S. (2023). "Effects of Δ9-tetrahydrocannabinol on mitochondria", in Mitochondrial Intoxication, Elsevier, pp. 451-473.

Preteroti, M., Wilson, E.T., Eidelman, D.H., and Baglole, C.J. (2023). "Modulation of pulmonary immune function by inhaled cannabis products and consequences for lung disease", Respiratory Research, Vol. 24 No. 1, pp. 95.

Rahman, A.M.D., Nemoto, K., Matsushima, K.I., Uddin, S.B., and Sarwar, A.K.M.G. (2022). "A history of cannabis (Ganja) as an economic crop in Bangladesh from the late 18th century to 1989 (1)", Japanese Society for Tropical Agriculture, Vol. 66 No. 1, pp. 21-32.

Reece, A.S., and Hulse, G.K. (2016). "Chromothripsis and epigenomics complete causality criteria for cannabis- and addiction-connected carcinogenicity, congenital toxicity and heritable genotoxicity", Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 789, pp. 15-25.

Reece, A.S., and Hulse, G.K. (2023). "Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: Part 1- aging and epigenomics", Frontiers in Psychiatry, Vol. 14, pp. 1182535.

Rong, C., Carmona, N.E., Lee, Y.L., Ragguett, R.M., Pan, Z., Rosenblat, J.D., Subramaniapillai, M., Shekotikhina, M., Almatham, F., Alageel, A., Mansur, R., Ho, R.C., and McIntyre, R.S. (2018). "Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents", Expert Opinion on Drug Safety, Vol. 17 No. 1, pp. 51-54.

Russo, C., Ferk, F., Mišík, M., Ropek, N., Nersesyan, A., Mejri, D., Holzmann, K., Lavorgna, M., Isidori, M., and Knasmüller, S. (2019). "Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells", Archives of Toxicology, Vol. 93 No. 1, pp. 179-188.

Salazar, M., Carracedo, A., Salanueva, Í.J., Hernández-Tiedra, S., Lorente, M., Egia, A., Vázquez, P., Blázquez, C., Torres, S., García, S., Nowak, J., Fimia, G.M., Piacentini, M., Cecconi, F., Pandolfi, P.P., González-Feria, L., Iovanna, J.L., Guzmán, M., Boya, P., and Velasco, G. (2009). "Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells", The Journal of Clinical Investigation, Vol. 119 No. 5, pp. 1359-1372.

Scott Bitner, R. (2012). "Cyclic AMP response element-binding protein (CREB) phosphorylation: A mechanistic marker in the development of memory enhancing Alzheimer’s disease therapeutics", Biochemical Pharmacology, Vol. 83 No. 6, pp. 705-714.

Scuderi, C., Filippis, D.D., Iuvone, T., Blasio, A., Steardo, A., and Esposito, G. (2009). "Cannabidiol in medicine: A review of its therapeutic potential in CNS disorders", Phytotherapy Research, Vol. 23 No. 5, pp. 597-602.

Sharma, P., Murthy, P., and Bharath, M.M.S. (2012). "Chemistry, Metabolism, and toxicology of cannabis: clinical implications", Iranian Journal of Psychiatry, Vol. 7 No. 4, pp. 149-156.

Sheikh, M.R., Mahmud, H.H., Hossen, M.S., Saha, D., Uddin, M.E., Hossain, M.F., Munshi, M.K., and Sina, A. A.I. (2025). "Modeling the interactions between chemicals and proteins to predict the health consequences of air pollution", International Journal of Environmental Research and Public Health, Vol. 22 No. 3, pp. 418.

Suliman, N.A., Taib, C.N.M., Moklas, M.A.M., and Basir, R. (2018). "Delta-9-tetrahydrocannabinol (∆9-THC) induce neurogenesis and improve cognitive performances of male Sprague Dawley rats", Neurotoxicity Research, Vol. 33 No. 2, pp. 402-411.

Szklarczyk, D., Kirsch, R., Koutrouli, M., Nastou, K., Mehryary, F., Hachilif, R., Gable, A.L., Fang, T., Doncheva, N.T., Pyysalo, S., Bork, P., Jensen, L.J., and von Mering, C. (2023). "The STRING database in 2023: Protein–protein association networks and functional enrichment analyses for any sequenced genome of interest", Nucleic Acids Research, Vol. 51 No. (D1), pp. D638-D646.

Voth, E.A. (1997). "Medicinal applications of Delta-9-Tetrahydrocannabinol and marijuana", Annals of Internal Medicine, Vol. 126 No. 10, pp. 791.

Walker, O.S., Ragos, R., Gurm, H., Lapierre, M., May, L.L., and Raha, S. (2020). "Delta‐9‐tetrahydrocannabinol disrupts mitochondrial function and attenuates syncytialization in human placental BeWo cells", Physiological Reports, Vol. 8 No. 13, pp. e14476.

Wilson, J., Freeman, T.P., and Mackie, C.J. (2019). "Effects of increasing cannabis potency on adolescent health", The Lancet Child & Adolescent Health, Vol. 3 No. 2, pp. 121-128.