Melittin Peptitlerinin CD147 Reseptörü ile Etkileşimindeki Antikanser Potansiyeli: Ligand-Reseptör Etkileşiminin Yapısal ve Fonksiyonel Analizi
Öz
Bu araştırmada, antikanser etkileriyle bilinen melittin (MLT) peptitlerinin CD147 reseptörüyle etkileşimlerinin antikanser potansiyeli in silico yapısal ve işlevsel analizlerle araştırılmıştır. CD147 transmembran glikoproteini ve siklofilinA (CypA) etkileşimi, kanser patolojisinde önemli olan sinyal yollarını aktive eder. Bu çalışmada, melittin peptitlerinin bu etkileşimi engelleme potansiyeli üzerinde durulmuştur. CD147 reseptör yapısı ve melittin peptit yapıları Protein Veri Bankası'ndan (PDB) temin edilmiş olup; bunlar arasında CD147'nin Ig1 alanının üç boyutlu yapısı (PDB No: 5XF0) ve melittin yapıları (PDB No: 2MLT, 6O4M, 3QRX, 8AHT ve 8AHS) bulunmaktadır. PDB tarafından onaylanmış ligand yapıları X-ışını kırınımı ile elde edilmiştir. ClusPro2.0 moleküler bağlanma sunucusu, AnciCP2.0 ve ENNAACT antikanser analiz sunucuları, ProtScale hidrofobisite analiz, PDBSum aminoasit etkileşim analiz ve PRODIGY termodinamik stabilite analiz araçları kullanılarak reseptör-ligand etkileşimleri ve antikanser aktivite değerlendirildi. Moleküler bağlanma simülasyonları reseptör-ligand etkileşimlerini analiz etmiş ve hidrofobik etkileşimlerin rolünü vurgulamıştır. Yapısal analiz, peptit kalitesinde değişkenlikleri göstermiş; 2MLT olumlu özellikler sergilerken, 3QRX’in zayıf bütünlük gösterdiği tespit edilmiştir. Antikanser analiz sunucuları 5XF0 ve CD147/CypA ile benzer bağlanma desenleri sergileyen 2MLT ve 3QRX'in her ikisinin de potansiyel antikanser aktivitesi gösterebileceğini ortaya koymuştur. Özellikle 5XF0-2MLT kompleksindeki Gly181 ve Arg201 ile bağsız etkileşimler, 5XF0-3QRX kompleksindeki Pro180, Gly181 ve Arg201 ile bağsız etkileşimler çalışmamızda ortaya konularak CD147/CypA etkileşim şekline benzerliğine dikkat çekilmiştir. Bu nedenle, moleküler etkileşimlerin anlaşılması ve ilaç keşfini yönlendirmenin önemi, yapısal incelemeler ve hesaplamalı analizlerin vurgulanarak, bu komplekslerin antikanser etkileri ve ilaç tasarımı üzerindeki etkilerine dair bilgiler sunulmuştur; ayrıca, bu yapısal belirleyicilerin ve terapötik potansiyellerinin ileri araştırmaları, biyomedikal uygulamalar için kritik öneme sahiptir.
Anahtar Kelimeler
Antikanser peptitler CD147 Melittin Moleküler bağlanma Siklofilin A
Kaynakça
- Agrawal, P., Bhagat, D., Mahalwal, M., Sharma, N., & Raghava, G. P. S. (2021). AntiCP 2.0: an updated model for predicting anticancer peptides. Briefings in Bioinformatics, 22(3), bbaa153.
- Bakhtiyari, M., Haji Aghasi, A., Banihashemi, S., Abbassioun, A., Tavakol, C., & Zalpoor, H. (2023). CD147 and cyclophilin A: a promising potential targeted therapy for COVID-19 and associated cancer progression and chemo-resistance. Infectious Agents and Cancer, 18(1), 20.
- Chaisakul, J., Hodgson, W. C., Kuruppu, S., & Prasongsook, N. (2016). Effects of animal venoms and toxins on hallmarks of cancer. Journal of Cancer, 7(11), 1571.
- Daniluk, K., Lange, A., Pruchniewski, M., Małolepszy, A., Sawosz, E., & Jaworski, S. (2022). Delivery of melittin as a lytic agent via graphene nanoparticles as carriers to breast cancer cells. Journal of Functional Biomaterials, 13(4), 278.
- Desta, I. T., Porter, K. A., Xia, B., Kozakov, D., & Vajda, S. (2020). Performance and its limits in rigid-body protein-protein docking. Structure, 28(9), 1071–1081.
- Dürvanger, Z., Juhász, T., Liliom, K., & Harmat, V. (2023). Structures of calmodulin–melittin complexes show multiple binding modes lacking classical anchoring interactions. Journal of Biological Chemistry, 299(4).
- Eisenberg, D., Gribskov, M., & Terwilliger, T. C. (1990). Melittin. Retrieved from https://doi.org/10.2210/pdb2MLT/pdb
- Gomes, A., Bhattacharjee, P., Mishra, R., Biswas, A. K., Dasgupta, S. C., Giri, B., Debnath, A., Gupta, S. Das, Das, T., & Gomes, A. (2010). Anticancer potential of animal venoms and toxins.
- Han, J. M., & Jung, H. J. (2022). Cyclophilin A/CD147 interaction: A promising target for anticancer therapy. International Journal of Molecular Sciences, 23(16), 9341.
- Haque, S., Hussain, A., Joshi, H., Sharma, U., Sharma, B., Aggarwal, D., Rani, I., Ramniwas, S., Gupta, M., & Tuli, H. S. (2023). Melittin: a possible regulator of cancer proliferation in preclinical cell culture and animal models. Journal of Cancer Research and Clinical Oncology, 149(19), 17709–17726.
- Huang, D., Rao, D., Jin, Q., Lai, M., Zhang, J., Lai, Z., Shen, H., & Zhong, T. (2023). Role of CD147 in the development and diagnosis of hepatocellular carcinoma. Frontiers in Immunology, 14, 1149931.
- Huang, S., Jianhua, W., Xiaozhong, W., & Chenghong, L. I. (2016). Melittin: A key composition of honey bee venom with diverse pharmaceutical functions. Paper presented at the International Conference on Biological Engineering and Pharmacy 2016 (BEP 2016), 193–197.
- Jin, S., Ding, P., Chu, P., Li, H., Sun, J., Liang, D., Song, F., & Xia, B. (2018). Zn(II) can mediate self-association of the extracellular C-terminal domain of CD147. Protein & Cell, 9(3), 310–315. https://doi.org/10.1007/s13238-017-0443-1
- Kozakov, D., Beglov, D., Bohnuud, T., Mottarella, S. E., Xia, B., Hall, D. R., & Vajda, S. (2013). How good is automated protein docking? Proteins: Structure, Function, and Bioinformatics, 81(12), 2159–2166.
- Kozakov, D., Hall, D. R., Xia, B., Porter, K. A., Padhorny, D., Yueh, C., Beglov, D., & Vajda, S. (2017). The ClusPro web server for protein-protein docking. Nature Protocols, 12(2), 255–278.
- Kurgan, K. W., Kleman, A. F., Bingman, C. A., Kreitler, D. F., Weisblum, B., Forest, K. T., & Gellman, S. H. (2019). Retention of native quaternary structure in racemic melittin crystals. Journal of the American Chemical Society, 141(19), 7704–7708.
- Li, L., Huang, J., & Lin, Y. (2018). Snake venoms in cancer therapy: past, present and future. Toxins, 10(9), 346. Memariani, H., Memariani, M., Shahidi-Dadras, M., Nasiri, S., Akhavan, M. M., & Moravvej, H. (2019). Melittin: from honeybees to superbugs. Applied Microbiology and Biotechnology, 103, 3265–3276.
- Nyalali, A. M. K., Leonard, A. U., Xu, Y., Li, H., Zhou, J., Zhang, X., Rugambwa, T. K., Shi, X., & Li, F. (2023). CD147: an integral and potential molecule to abrogate hallmarks of cancer. Frontiers in Oncology, 13.
- Oner, E., Demirhan, I., Kurutas, EB., & Yalin, S (2024). Investigation of Active Compounds in Propolis Structure Against Sars Cov-2 Main Protease by Molecular Docking Method: In Silico Study. Journal Of Agriculture and Nature 27(1), 46–55. https://doi.org/10.18016/ksutarimdoga.vi.1093707.
- Pandey, P., Khan, F., Khan, M. A., Kumar, R., & Upadhyay, T. K. (2023). An updated review summarizing the anticancer efficacy of melittin from bee venom in several models of human cancers. Nutrients, 15(14), 3111.
- Roy, A., & Bharadvaja, N. (2021). Venom-derived bioactive compounds as potential anticancer agents: a review. International Journal of Peptide Research and Therapeutics, 27, 129–147.
- Sjakste, N., & Gajski, G. (2023). A review on genotoxic and genoprotective effects of biologically active compounds of animal origin. Toxins, 15(2), 165.
- Sosa, L. del V., Alfaro, E., Santiago, J., Narváez, D., Rosado, M. C., Rodríguez, A., Gómez, A. M., Schreiter, E. R., & Pastrana‐Ríos, B. (2011). The structure, molecular dynamics, and energetics of centrin–melittin complex. Proteins: Structure, Function, and Bioinformatics, 79(11), 3132–3143.
- Timmons, P. B., & Hewage, C. M. (2021). ENNAACT is a novel tool that employs neural networks for anticancer activity classification for therapeutic peptides. Biomedicine & Pharmacotherapy, 133, 111051.
- Tiwari, R., Tiwari, G., Lahiri, A., Ramachandran, V., & Rai, A. (2022). Melittin: a natural peptide with expanded therapeutic applications. The Natural Products Journal, 12(2), 13–29.
- Xiong, L., Edwards III, C. K., & Zhou, L. (2014). The biological function and clinical utilization of CD147 in human diseases: a review of the current scientific literature. International Journal of Molecular Sciences, 15(10), 17411–17441.
- Yang, Z., Zang, Y., Wang, H., Kang, Y., Zhang, J., Li, X., Zhang, L., & Zhang, S. (2022). Recognition between CD147 and cyclophilin A deciphered by accelerated molecular dynamics simulations. Physical Chemistry Chemical Physics, 24(31), 18905–18914.
- Yurchenko, V., Constant, S., Eisenmesser, E., & Bukrinsky, M. (2010). Cyclophilin–CD147 interactions: a new target for anti-inflammatory therapeutics. Clinical & Experimental Immunology, 160(3), 305–317.
Unveiling Anticancer Potential in the Interactions of Melittin Peptides with CD147 Receptor: A Structural and Functional Analysis of Ligand-Target Interactions
Öz
In this study, the anticancer potential of melittin (MLT) peptides interacting with the CD147 receptor was investigated through in silico structural and functional analyses. The interaction between the transmembrane glycoprotein CD147 and cyclophilin A (CypA) activates signaling pathways crucial in cancer pathology. This study focused on the potential of melittin peptides to inhibit this interaction. Structures of the CD147 receptor and melittin peptides were obtained from the Protein Data Bank (PDB), including the three-dimensional structure of the Ig1 domain of CD147 (PDB ID: 5XF0) and melittin structures (PDB IDs: 2MLT, 6O4M, 3QRX, 8AHT, and 8AHS). Validated ligand structures were acquired through X-ray crystallography. Receptor-ligand interactions and anticancer activity were evaluated using the ClusPro2.0 molecular docking server, AnciCP2.0 and ENNAACT anticancer analysis servers, ProtScale hydrophobicity analysis, PDBSum amino acid interaction analysis, and PRODIGY thermodynamic stability analysis tools. Molecular docking simulations analyzed receptor-ligand interactions, emphasizing the role of hydrophobic interactions. Structural analysis revealed variability in peptide quality, with 2MLT demonstrating favorable attributes while 3QRX exhibited weak integrity. Anticancer analysis servers indicated that 2MLT and 3QRX, exhibiting similar binding patterns with 5XF0 and CD147/CypA, may demonstrate potential anticancer activity. Specifically, non-bonded interactions involving Gly181 and Arg201 in the 5XF0-2MLT complex and non-bonded interactions involving Pro180, Gly181, and Arg201 in the 5XF0-3QRX complex were highlighted, resembling the interaction pattern of CD147/CypA. Therefore, the importance of understanding molecular interactions and guiding drug discovery through structural examinations and computational analyses was emphasized, providing insights into the anticancer effects and drug design implications of these complexes; moreover, further research into their structural determinants and therapeutic potentials is critically essential for biomedical applications.
Anahtar Kelimeler
Anti-cancer peptides CD147 Cyclophilin A Melittin Molecular docking
Kaynakça
- Agrawal, P., Bhagat, D., Mahalwal, M., Sharma, N., & Raghava, G. P. S. (2021). AntiCP 2.0: an updated model for predicting anticancer peptides. Briefings in Bioinformatics, 22(3), bbaa153.
- Bakhtiyari, M., Haji Aghasi, A., Banihashemi, S., Abbassioun, A., Tavakol, C., & Zalpoor, H. (2023). CD147 and cyclophilin A: a promising potential targeted therapy for COVID-19 and associated cancer progression and chemo-resistance. Infectious Agents and Cancer, 18(1), 20.
- Chaisakul, J., Hodgson, W. C., Kuruppu, S., & Prasongsook, N. (2016). Effects of animal venoms and toxins on hallmarks of cancer. Journal of Cancer, 7(11), 1571.
- Daniluk, K., Lange, A., Pruchniewski, M., Małolepszy, A., Sawosz, E., & Jaworski, S. (2022). Delivery of melittin as a lytic agent via graphene nanoparticles as carriers to breast cancer cells. Journal of Functional Biomaterials, 13(4), 278.
- Desta, I. T., Porter, K. A., Xia, B., Kozakov, D., & Vajda, S. (2020). Performance and its limits in rigid-body protein-protein docking. Structure, 28(9), 1071–1081.
- Dürvanger, Z., Juhász, T., Liliom, K., & Harmat, V. (2023). Structures of calmodulin–melittin complexes show multiple binding modes lacking classical anchoring interactions. Journal of Biological Chemistry, 299(4).
- Eisenberg, D., Gribskov, M., & Terwilliger, T. C. (1990). Melittin. Retrieved from https://doi.org/10.2210/pdb2MLT/pdb
- Gomes, A., Bhattacharjee, P., Mishra, R., Biswas, A. K., Dasgupta, S. C., Giri, B., Debnath, A., Gupta, S. Das, Das, T., & Gomes, A. (2010). Anticancer potential of animal venoms and toxins.
- Han, J. M., & Jung, H. J. (2022). Cyclophilin A/CD147 interaction: A promising target for anticancer therapy. International Journal of Molecular Sciences, 23(16), 9341.
- Haque, S., Hussain, A., Joshi, H., Sharma, U., Sharma, B., Aggarwal, D., Rani, I., Ramniwas, S., Gupta, M., & Tuli, H. S. (2023). Melittin: a possible regulator of cancer proliferation in preclinical cell culture and animal models. Journal of Cancer Research and Clinical Oncology, 149(19), 17709–17726.
- Huang, D., Rao, D., Jin, Q., Lai, M., Zhang, J., Lai, Z., Shen, H., & Zhong, T. (2023). Role of CD147 in the development and diagnosis of hepatocellular carcinoma. Frontiers in Immunology, 14, 1149931.
- Huang, S., Jianhua, W., Xiaozhong, W., & Chenghong, L. I. (2016). Melittin: A key composition of honey bee venom with diverse pharmaceutical functions. Paper presented at the International Conference on Biological Engineering and Pharmacy 2016 (BEP 2016), 193–197.
- Jin, S., Ding, P., Chu, P., Li, H., Sun, J., Liang, D., Song, F., & Xia, B. (2018). Zn(II) can mediate self-association of the extracellular C-terminal domain of CD147. Protein & Cell, 9(3), 310–315. https://doi.org/10.1007/s13238-017-0443-1
- Kozakov, D., Beglov, D., Bohnuud, T., Mottarella, S. E., Xia, B., Hall, D. R., & Vajda, S. (2013). How good is automated protein docking? Proteins: Structure, Function, and Bioinformatics, 81(12), 2159–2166.
- Kozakov, D., Hall, D. R., Xia, B., Porter, K. A., Padhorny, D., Yueh, C., Beglov, D., & Vajda, S. (2017). The ClusPro web server for protein-protein docking. Nature Protocols, 12(2), 255–278.
- Kurgan, K. W., Kleman, A. F., Bingman, C. A., Kreitler, D. F., Weisblum, B., Forest, K. T., & Gellman, S. H. (2019). Retention of native quaternary structure in racemic melittin crystals. Journal of the American Chemical Society, 141(19), 7704–7708.
- Li, L., Huang, J., & Lin, Y. (2018). Snake venoms in cancer therapy: past, present and future. Toxins, 10(9), 346. Memariani, H., Memariani, M., Shahidi-Dadras, M., Nasiri, S., Akhavan, M. M., & Moravvej, H. (2019). Melittin: from honeybees to superbugs. Applied Microbiology and Biotechnology, 103, 3265–3276.
- Nyalali, A. M. K., Leonard, A. U., Xu, Y., Li, H., Zhou, J., Zhang, X., Rugambwa, T. K., Shi, X., & Li, F. (2023). CD147: an integral and potential molecule to abrogate hallmarks of cancer. Frontiers in Oncology, 13.
- Oner, E., Demirhan, I., Kurutas, EB., & Yalin, S (2024). Investigation of Active Compounds in Propolis Structure Against Sars Cov-2 Main Protease by Molecular Docking Method: In Silico Study. Journal Of Agriculture and Nature 27(1), 46–55. https://doi.org/10.18016/ksutarimdoga.vi.1093707.
- Pandey, P., Khan, F., Khan, M. A., Kumar, R., & Upadhyay, T. K. (2023). An updated review summarizing the anticancer efficacy of melittin from bee venom in several models of human cancers. Nutrients, 15(14), 3111.
- Roy, A., & Bharadvaja, N. (2021). Venom-derived bioactive compounds as potential anticancer agents: a review. International Journal of Peptide Research and Therapeutics, 27, 129–147.
- Sjakste, N., & Gajski, G. (2023). A review on genotoxic and genoprotective effects of biologically active compounds of animal origin. Toxins, 15(2), 165.
- Sosa, L. del V., Alfaro, E., Santiago, J., Narváez, D., Rosado, M. C., Rodríguez, A., Gómez, A. M., Schreiter, E. R., & Pastrana‐Ríos, B. (2011). The structure, molecular dynamics, and energetics of centrin–melittin complex. Proteins: Structure, Function, and Bioinformatics, 79(11), 3132–3143.
- Timmons, P. B., & Hewage, C. M. (2021). ENNAACT is a novel tool that employs neural networks for anticancer activity classification for therapeutic peptides. Biomedicine & Pharmacotherapy, 133, 111051.
- Tiwari, R., Tiwari, G., Lahiri, A., Ramachandran, V., & Rai, A. (2022). Melittin: a natural peptide with expanded therapeutic applications. The Natural Products Journal, 12(2), 13–29.
- Xiong, L., Edwards III, C. K., & Zhou, L. (2014). The biological function and clinical utilization of CD147 in human diseases: a review of the current scientific literature. International Journal of Molecular Sciences, 15(10), 17411–17441.
- Yang, Z., Zang, Y., Wang, H., Kang, Y., Zhang, J., Li, X., Zhang, L., & Zhang, S. (2022). Recognition between CD147 and cyclophilin A deciphered by accelerated molecular dynamics simulations. Physical Chemistry Chemical Physics, 24(31), 18905–18914.
- Yurchenko, V., Constant, S., Eisenmesser, E., & Bukrinsky, M. (2010). Cyclophilin–CD147 interactions: a new target for anti-inflammatory therapeutics. Clinical & Experimental Immunology, 160(3), 305–317.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Veteriner Bilimleri (Diğer) |
| Bölüm | ARAŞTIRMA MAKALESİ (Research Article) |
| Yazarlar | |
| Erken Görünüm Tarihi | 19 Aralık 2024 |
| Yayımlanma Tarihi | |
| Gönderilme Tarihi | 18 Nisan 2024 |
| Kabul Tarihi | 7 Kasım 2024 |
| Yayımlandığı Sayı | Yıl 2024Cilt: 27 Sayı: Ek Sayı 2 (Suppl 2) |
Kaynak Göster
2022-JIF = 0.500
2022-JCI = 0.170
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