Moleküler Yerleştirme Yöntemi ile Kanabidiolün Reseptör-Ligant Etkileşiminin İncelenmesi

Year 2023, Volume: 13 Issue: 2, 398 - 414, 15.06.2023

Emre Fatih Ediz Meltem Demirel Kars

https://doi.org/10.31466/kfbd.1214649

Abstract

Kanabidiol, CB1 ve CB2 reseptörlerine düşük bağlanma eğilimine (afiniteye) sahip ve psikoaktif özellikleri olmayan bir kanabinoiddir. Ayrıca G proteinine bağlı reseptörler, serotonin reseptörleri ve opioid reseptörleri ile de aktivite göstermektedir. Bu nedenle kanabidiol uzun zamandır anksiyete, depresyon, refrakter epilepsi gibi nöronal hastalıkların, Parkinson, Alzheimer hastalığı, amyotrofik lateral skleroz gibi sinir sistemi hastalıklarının, enflamatuvar bozukluklar gibi bağışıklık sistemi hastalıklarının tedavisinde kullanılmaktadır. Ayrıca opioid reseptörleri ile güçlü aktivitesi sayesinde yoksunluk sendromu tedavisinde de kullanılmaktadır. Bu çalışmada iki klasik kanabinoid reseptörü olan CB1 ve CB2, bunlara ilaveten literatür taramaları sonucunda, İnsan Delta-Opioid Reseptörü (δ-OP), Nosiseptin/Orfanin FQ receptor (G protein-coupled receptor 55 - GPR55), Vanilloid Reseptörü (Transient receptor potential vanilloid receptor1 -TRPV1) ve Serotonin 1A reseptörü (5-HT1A) tercih edilmiştir. Yapılan moleküler yerleştirme çalışmaları sonucunda CBD'nin CB1, CB2, δ-OP, GPR55, TRPV1 ve 5-HT1A reseptörleri için önemli afiniteye sahip bir molekül olduğu gösterilmiştir.

Keywords

Kanabidiol, ligant, reseptör, moleküler yerleştirme

Supporting Institution

Tübitak

Project Number

119C100

Thanks

Bu çalışma TÜBİTAK 2244 Üniversite Sanayi İşbirliği Projesi (119C100) tarafından desteklenmektedir.

Investigation of Receptor-Ligand Interaction of Cannabidiol by Molecular Docking Method

Abstract

Cannabidiol is a cannabinoid that has low affinity for CB1 and CB2 receptors and does not have psychoactive properties. It also exhibits activity with G protein-coupled receptors, serotonin receptors and opioid receptors. Therefore, cannabidiol has been used for a long time in the treatment of neuronal diseases such as anxiety, depression, refractory epilepsy, nervous system diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and immune system diseases such as inflammatory disorders. In this study, two classical cannabinoid receptors, CB1 and CB2, and Human Delta-Opioid Receptor (δ-OP), Nociceptin/Orphanin FQ receptor (G protein-coupled receptor 55 - GPR55), Vanilloid Receptor (Transient receptor potential vanilloid receptor1 -TRPV1)) and Serotonin 1A receptor (5-HT1A) were selected in addition to the so called receptors, as a result of literature review. As a result of molecular docking studies, it has been revealed that CBD is a molecule with significant affinity for CB1, CB2, δ-OP, GPR55, TRPV1 and 5-HT1A receptors.

Keywords

Cannabidiol, ligand, receptor, molecular docking

Project Number

119C100

References

• Abelian, A., Dybek, M., Wallach, J., Gaye, B., & Adejare, A. (2021). Pharmaceutical chemistry. In Remington (pp. 105-128). Academic Press.
• Anand, U., Jones, B., Korchev, Y., Bloom, S. R., Pacchetti, B., Anand, P., & Sodergren, M. H. (2020). CBD effects on TRPV1 signaling pathways in cultured DRG neurons. Journal of Pain Research, 13, 2269. https://doi.org/10.2147/jpr.s258433
• Arthur, D. E., ve Uzairu, A. (2019). Molecular docking studies on the interaction of NCI anticancer analogues with human Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit. In Journal of King Saud University - Science (Vol. 31, Issue 4, pp. 1151–1166). Elsevier BV. https://doi.org/10.1016/j.jksus.2019.01.011
• Aviz-Amador, A., Contreras-Puentes, N., & Mercado-Camargo, J. (2021). Virtual screening using docking and molecular dynamics of cannabinoid analogs against CB1 and CB2 receptors. In Computational Biology and Chemistry (Vol. 95, p. 107590). Elsevier BV. https://doi.org/10.1016/j.compbiolchem.2021.107590
• Beaulieu, P. (2005). Toxic Effects of Cannabis and Cannabinoids: Animal Data. In Pain Research and Management (Vol. 10, Issue suppl a, pp. 23A-26A). Hindawi Limited. https://doi.org/10.1155/2005/763623
• Berman, H. M. (2000). The Protein Data Bank. In Nucleic Acids Research (Vol. 28, Issue 1, pp. 235–242). Oxford University Press (OUP). https://doi.org/10.1093/nar/28.1.235
• Bibi, S., & Sakata, K. (2017). An Integrated Computational Approach for Plant-Based Protein Tyrosine Phosphatase Non-Receptor Type 1 Inhibitors. In Current Computer-Aided Drug Design (Vol. 13, Issue 4). Bentham Science Publishers Ltd. https://doi.org/10.2174/1573409913666170406145607
• Cortez, I. L., Rodrigues da Silva, N., Guimarães, F. S., & Gomes, F. V. (2020). Are CB2 Receptors a New Target for Schizophrenia Treatment? In Frontiers in Psychiatry (Vol. 11). Frontiers Media SA. https://doi.org/10.3389/fpsyt.2020.587154
• Crampon, K., Giorkallos, A., Deldossi, M., Baud, S., & Steffenel, L. A. (2022). Machine-learning methods for ligand–protein molecular docking. In Drug Discovery Today (Vol. 27, Issue 1, pp. 151–164). Elsevier BV. https://doi.org/10.1016/j.drudis.2021.09.007
• Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. In Scientific Reports (Vol. 7, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/srep42717
• Dripps, I. J., Bertels, Z., Moye, L. S., Tipton, A. F., Siegersma, K., Baca, S. M., Kieffer, B. L., & Pradhan, A. A. (2020). Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia. In Scientific Reports (Vol. 10, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41598-020-74605-9
• Franzen, J. M., Werle, I., Vanz, F., de Oliveira, B. B., Martins Nascimento, L. M., Guimarães, F. S., & Bertoglio, L. J. (2023). Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT1A but not CB1 or CB2 receptors. In Neuropharmacology (Vol. 223, p. 109316). Elsevier BV. https://doi.org/10.1016/j.neuropharm.2022.109316
• Horowitz, S., & Trievel, R. C. (2012). Carbon-Oxygen Hydrogen Bonding in Biological Structure and Function. In Journal of Biological Chemistry (Vol. 287, Issue 50, pp. 41576–41582). Elsevier BV. https://doi.org/10.1074/jbc.r112.418574
• Howlett, A. C., & Abood, M. E. (2017). CB 1 and CB 2 Receptor Pharmacology. In Cannabinoid Pharmacology (pp. 169–206). Elsevier. https://doi.org/10.1016/bs.apha.2017.03.007
• Howlett, A., Blume, L., & Dalton, G. (2010). CB1 Cannabinoid Receptors and their Associated Proteins. In Current Medicinal Chemistry (Vol. 17, Issue 14, pp. 1382–1393). Bentham Science Publishers Ltd. https://doi.org/10.2174/092986710790980023
• Jimenez-Vargas, N. N., Gong, J., Wisdom, M. J., Jensen, D. D., Latorre, R., Hegron, A., Teng, S., DiCello, J. J., Rajasekhar, P., Veldhuis, N. A., Carbone, S. E., Yu, Y., Lopez-Lopez, C., Jaramillo-Polanco, J., Canals, M., Reed, D. E., Lomax, A. E., Schmidt, B. L., Leong, K. W., … Poole, D. P. (2020). Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain. In Proceedings of the National Academy of Sciences (Vol. 117, Issue 26, pp. 15281–15292). Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2000500117
• Kathmann, M., Flau, K., Redmer, A., Tränkle, C., & Schlicker, E. (2006). Cannabidiol is an allosteric modulator at mu-and delta-opioid receptors. Naunyn-Schmiedeberg's archives of pharmacology, 372(5), 354-361.
• Kimura, T., & Higaki, K. (2002). Gastrointestinal Transit and Drug Absorption. In Biological & Pharmaceutical Bulletin (Vol. 25, Issue 2, pp. 149–164). Pharmaceutical Society of Japan. https://doi.org/10.1248/bpb.25.149
• Kogan, N. M., & Mechoulam, R. (2007). Cannabinoids in health and disease. In Dialogues in Clinical Neuroscience (Vol. 9, Issue 4, pp. 413–430). Informa UK Limited. https://doi.org/10.31887/dcns.2007.9.4/nkogan
• Lagunin, A., Zakharov, A., Filimonov, D., & Poroikov, V. (2011). QSAR Modelling of Rat Acute Toxicity on the Basis of PASS Prediction. In Molecular Informatics (Vol. 30, Issues 2–3, pp. 241–250). Wiley. https://doi.org/10.1002/minf.201000151
• Lipinski, C. A. (2004). Lead- and drug-like compounds: the rule-of-five revolution. In Drug Discovery Today: Technologies (Vol. 1, Issue 4, pp. 337–341). Elsevier BV. https://doi.org/10.1016/j.ddtec.2004.11.007
• Liu, L. Y., Alexa, K., Cortes, M., Schatzman-Bone, S., Kim, A. J., Mukhopadhyay, B., Cinar, R., Kunos, G., North, T. E., & Goessling, W. (2016). Cannabinoid receptor signaling regulates liver development and metabolism. In Development (Vol. 143, Issue 4, pp. 609–622). The Company of Biologists. https://doi.org/10.1242/dev.121731
• Maroon, J., ve Bost, J. (2018). Review of the neurological benefits of phytocannabinoids. In Surgical Neurology International (Vol. 9, Issue 1, p. 91). Scientific Scholar. https://doi.org/10.4103/sni.sni_45_18
• Savitz, J., Lucki, I., & Drevets, W. C. (2009). 5-HT1A receptor function in major depressive disorder. In Progress in Neurobiology (Vol. 88, Issue 1, pp. 17–31). Elsevier BV. https://doi.org/10.1016/j.pneurobio.2009.01.009
• Silvestro, S., Mammana, S., Cavalli, E., Bramanti, P., & Mazzon, E. (2019). Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials. In Molecules (Vol. 24, Issue 8, p. 1459). MDPI AG. https://doi.org/10.3390/molecules24081459
• Stohs, S., & Ray, S. (2020). Is cannabidiol hepatotoxic or hepatoprotective: A review. In Toxicology Research and Application (Vol. 4, p. 239784732092294). SAGE Publications. https://doi.org/10.1177/2397847320922944
• Suttithumsatid, W., Shah, M. A., Bibi, S., & Panichayupakaranant, P. (2022). α-Glucosidase inhibitory activity of cannabidiol, tetrahydrocannabinol and standardized cannabinoid extracts from Cannabis sativa. In Current Research in Food Science (Vol. 5, pp. 1091–1097). Elsevier BV. https://doi.org/10.1016/j.crfs.2022.07.002
• Tütüncü, Ş., & Özfiliz, N. (2011). Vanilloid reseptör 1 (VR1)(Capsaicin reseptörü). Uludağ Üniversitesi Veteriner Fakültesi Dergisi, 30(2), 53-60.
• Whalley, B. J., Bazelot, M., Rosenberg, E., & Tsien, R. (2018). A role of GPR55 in the antiepileptic properties of cannabidiol (CBD)(P2. 277).
• Wu, H., Wacker, D., Mileni, M., Katritch, V., Han, G. W., Vardy, E., Liu, W., Thompson, A. A., Huang, X.-P., Carroll, F. I., Mascarella, S. W., Westkaemper, R. B., Mosier, P. D., Roth, B. L., Cherezov, V., & Stevens, R. C. (2012). Structure of the human κ-opioid receptor in complex with JDTic. In Nature (Vol. 485, Issue 7398, pp. 327–332). Springer Science and Business Media LLC. https://doi.org/10.1038/nature10939