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SARS-CoV-2 Ana Proteaz Enzimine Yönelik Antiviral Bileşiklerin Bilgisayar Destekli İlaç Tasarımı Yöntemleri ile Değerlendirilmesi

Year 2021, Issue: 32, 1043 - 1047, 31.12.2021
https://doi.org/10.31590/ejosat.1041077

Abstract

COVID-19, asemptomatik ya da hafif hastalık belirtilere sahip olup, hızlı ve şiddetli gelişen üst solunum yolları bulguları sonucunda ölüme kadar götürebilen ciddi bir hastalıktır. SARS-CoV-2'nin yeni tanımlanan bir virüs olması, kısa ve uzun dönem etkilerinin tam olarak bilinmemesi ve oluşturduğu etkilerin bireyler arasında farklılık göstermesi nedeniyle, COVID-19'un tanısı ve tedavisi güçleşmektedir. Bununla birlikte, yeni bir ilaç molekülünün keşfinde yaklaşık 5-10 bin aday molekül incelenmekte, bu aday moleküllerin arasından bir ilacın piyasaya sürülmesi 10 yıldan fazla bir zaman alabilmekte ve tüm sürecin maliyeti ise yaklaşık 330 milyon doları bulabilmektedir. İlaç keşfinin maliyetli ve zaman alan bir süreç olması göz önüne alındığında, COVID-19 pandemisine bağlı ölüm vakalarının dünya genelinde yüksek oranda seyretmesiyle birlikte bu hastalığı önleyici ve tedavi etme amaçlı ilaç ve aşı geliştirme yöntemlerinde yeni akılcı yaklaşımların önemi artmıştır. Son yıllarda bilgisayar teknolojilerindeki ilerlemelere birlikte ilaç geliştirme çalışmalarına yönelik bilgisayar destekli ilaç tasarımı (in siliko) yöntemleri geliştirilmiştir. Böylece, yüksek maliyetli ve zaman alıcı olan ıslak laboratuvar çalışmalar yerine, kısa sürede ve düşük maliyetle ilaç geliştirme süreci tamamlanabilmektedir. Bu çalışmada, bilgisayar destekli ilaç tasarım yöntemleri kullanılarak SARS-CoV-2'nin virülansında önemli rol oynayan ana proteaz (Mpro) ile çeşitli viral hastalıklar için klinik olarak kullanılan 15 adet antiviral bileşiğin biyolojik aktivitelerinin araştırılması hedeflenmiştir. Çalışmanın ilk adımında SARS-CoV-2’nin ana proteaz enzimi ve antiviral bileşiklerin 3-boyutlu yapı analizleri yapılmıştır. Ardından, bilgisayar destekli ilaç tasarımı yöntemi olan moleküler kenetlenme kullanılarak her bir antiviral bileşik ile hedef enzim arasındaki bağlanma serbest enerjisi ve inhibisyon katsayısı hesaplanmıştır. Yapılan bu analiz sonucunda, Lopinavir bileşiği SARS-CoV-2 ana proteazına karşı en iyi bağlanma affinitesi gösteren bileşik olarak belirlenmiştir. Ayrıca bu bileşik, SARS-CoV-2 ana proteazının aktivitesinde önemli role sahip olan Cys145, Glu166, Glu189 ve Ser144 aminoasitleri ile hidrojen bağı etkileşimi oluşturmuştur. Elde edilen sonuçlar, varolan antiviral ilaç molekülerinin biyolojik etkinliklerinin zaman ve maliyet açısından daha avantajlı sekilde irdelenmesini sağlamıştır. Bu çalışma COVID-19 tedavisine yönelik daha etkili antiviral ilaçların geliştirilmesine yönelik yapılacak klinik çalışmalara rehberlik edecektir.

Thanks

Bu çalışmada, moleküler docking yöntemine ait hesaplamalar için TRUBA kaynaklarının kullanılmasına olanak sağlayan TÜBİTAK ULAKBİM’e teşekkür ederiz

References

  • Amin, M., & Abbas, G. (2020). Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein – an in silico insight into the comparative efficacy of repurposing antiviral drugs. Journal of Biomolecular Structure and Dynamics, 1-13.
  • Banerjee, R., Perera, L., & Tillekeratne, L. M. V. (2021). Potential SARS-CoV-2 main protease inhibitors. Drug Discovery Today, 26(3), 804-816.
  • Cui, W., Yang, K., & Yang, H. (2020). Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19. Frontiers in Molecular Biosciences, 7.
  • Dassault Systèmes BIOVIA. Discovery Studio Modeling Environment, Release 2020. San Diego: Dassault Systèmes; 2020.
  • Erickson, J. W. (1993). Design and structure of symmetry-based inhibitors of HIV-1 protease. Perspectives in Drug Discovery and Design, 1(1), 109-128.
  • Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., … Yang, H. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289-293.
  • Jurrus, E., Engel, D., Star, K., Monson, K., Brandi, J., Felberg, L. E., Brookes, D. H., Wilson, L., Chen, J., Liles, K., Chun, M., Li, P., Gohara, D. W., Dolinsky, T., Konecny, R., Koes, D. R., Nielsen, J. E., Head‐Gordon, T., Geng, W., … Baker, N. A. (2018). Improvements to the APBS biomolecular solvation software suite. Protein Science, 27(1), 112-128.
  • Kaldor, S. W., Kalish, V. J., Davies, J. F., Shetty, B. V., Fritz, J. E., Appelt, K., Burgess, J. A., Campanale, K. M., Chirgadze, N. Y., Clawson, D. K., Dressman, B. A., Hatch, S. D., Khalil, D. A., Kosa, M. B., Lubbehusen, P. P., Muesing, M. A., Patick, A. K., Reich, S. H., Su, K. S., & Tatlock, J. H. (1997). Viracept (nelfinavir mesylate, AG1343): A potent, orally bioavailable inhibitor of HIV-1 protease. Journal of Medicinal Chemistry, 40(24), 3979-3985.
  • Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2019). PubChem 2019 update: Improved access to chemical data. Nucleic Acids Research, 47(D1), D1102-D1109.
  • Kumar, D., Kumari, K., Vishvakarma, V. K., Jayaraj, A., Kumar, D., Ramappa, V. K., Patel, R., Kumar, V., Dass, S. K., Chandra, R., & Singh, P. (2020). Promising inhibitors of main protease of novel corona virus to prevent the spread of COVID-19 using docking and molecular dynamics simulation. Journal of Biomolecular Structure and Dynamics, 1-15.
  • Li, Z., Li, X., Huang, Y.-Y., Wu, Y., Liu, R., Zhou, L., Lin, Y., Wu, D., Zhang, L., Liu, H., Xu, X., Yu, K., Zhang, Y., Cui, J., Zhan, C.-G., Wang, X., & Luo, H.-B. (2020). Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs. Proceedings of the National Academy of Sciences, 117(44), 27381-27387.
  • Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. Journal of computational chemistry, 30(16), 2785-2791.
  • Rich, D. H., Sun, C. Q., Prasad, J. V. N. V., Pathiasseril, A., Toth, M. V., Marshall, G. R., Clare, M., Mueller, R. A., & Houseman, K. (1991). Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes. Journal of Medicinal Chemistry, 34(3), 1222-1225.
  • Roberts, N. A., Martin, J. A., Kinchington, D., Broadhurst, A. V., Craig, J. C., Duncan, I. B., Galpin, S. A., Handa, B. K., Kay, J., & Kröhn, A. (1990). Rational design of peptide-based HIV proteinase inhibitors. Science (New York, N.Y.), 248(4953), 358-361.
  • Solis-Vasquez, L., Santos-Martins, D., Koch, A., & Forli, S. (2020). Evaluating the Energy Efficiency of OpenCL-accelerated AutoDock Molecular Docking. 2020 28th Euromicro International Conference on Parallel, Distributed and Network-Based Processing (PDP), 162-166.
  • Summa, V., Petrocchi, A., Bonelli, F., Crescenzi, B., Donghi, M., Ferrara, M., Fiore, F., Gardelli, C., Gonzalez Paz, O., Hazuda, D. J., Jones, P., Kinzel, O., Laufer, R., Monteagudo, E., Muraglia, E., Nizi, E., Orvieto, F., Pace, P., Pescatore, G., … Rowley, M. (2008). Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection. Journal of Medicinal Chemistry, 51(18), 5843-5855.
  • Wu, A., Peng, Y., Huang, B., Ding, X., Wang, X., Niu, P., Meng, J., Zhu, Z., Zhang, Z., Wang, J., Sheng, J., Quan, L., Xia, Z., Tan, W., Cheng, G., & Jiang, T. (2020). Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell Host & Microbe, 27(3), 325-328.
  • Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., & Hilgenfeld, R. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 368(6489), 409-412.

Evaluation of Antiviral Compounds Against SARS-CoV-2 Main Protease Enzyme by Computer Aided Drug Design Methods

Year 2021, Issue: 32, 1043 - 1047, 31.12.2021
https://doi.org/10.31590/ejosat.1041077

Abstract

COVID-19 is a serious disease that has asymptomatic or mild disease symptoms and can lead to death as a result of rapid and severe upper respiratory tract findings. Since SARS-CoV-2 is a newly identified virus, its short and long-term effects are not fully known, and the effects it creates differ between individuals, the diagnosis and treatment of COVID-19 becomes difficult. However, in the discovery of a new drug molecule, approximately 5-10 thousand candidate molecules are examined, it may take more than 10 years to launch a drug among these candidate molecules, and the cost of the whole process can reach approximately 330 million dollars. Considering that drug discovery is a costly and time-consuming process, with the high rate of death cases due to the COVID-19 pandemic worldwide, the importance of new rational approaches in the development of preventive and therapeutic drugs and vaccines has increased. In recent years, computer-aided drug design (in silico) methods have been developed for drug development studies with the advances in computer technologies. Thus, instead of high-cost and time-consuming wet laboratory studies, the drug development process can be completed in a short time and at low cost. In this study, it was aimed to investigate the biological activities of the main protease (Mpro), which plays an important role in the virulence of SARS-CoV-2, and 15 antiviral compounds used clinically for various viral diseases by using computer aided drug design methods. In the first step of the study, 3-dimensional structure analyzes of the main protease enzyme of SARS-CoV-2 and antiviral compounds were performed. Then, the binding free energy and inhibition constant between each antiviral compound and the target enzyme were calculated using molecular docking, which is a computer aided drug design method. As a result of this analysis, Lopinavir compound was determined as the compound with the best binding affinity against SARS-CoV-2 main protease. In addition, this compound formed a hydrogen bond interaction with Cys145, Glu166, Glu189 and Ser144 aminoacids, which have an important role in the activity of SARS-CoV-2 main protease. The results obtained provided a more advantageous examination of the biological activities of the existing antiviral drug molecules in terms of time and cost. This study will guide clinical studies to develop more effective antiviral drugs for the treatment of COVID-19.

References

  • Amin, M., & Abbas, G. (2020). Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein – an in silico insight into the comparative efficacy of repurposing antiviral drugs. Journal of Biomolecular Structure and Dynamics, 1-13.
  • Banerjee, R., Perera, L., & Tillekeratne, L. M. V. (2021). Potential SARS-CoV-2 main protease inhibitors. Drug Discovery Today, 26(3), 804-816.
  • Cui, W., Yang, K., & Yang, H. (2020). Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19. Frontiers in Molecular Biosciences, 7.
  • Dassault Systèmes BIOVIA. Discovery Studio Modeling Environment, Release 2020. San Diego: Dassault Systèmes; 2020.
  • Erickson, J. W. (1993). Design and structure of symmetry-based inhibitors of HIV-1 protease. Perspectives in Drug Discovery and Design, 1(1), 109-128.
  • Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., … Yang, H. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289-293.
  • Jurrus, E., Engel, D., Star, K., Monson, K., Brandi, J., Felberg, L. E., Brookes, D. H., Wilson, L., Chen, J., Liles, K., Chun, M., Li, P., Gohara, D. W., Dolinsky, T., Konecny, R., Koes, D. R., Nielsen, J. E., Head‐Gordon, T., Geng, W., … Baker, N. A. (2018). Improvements to the APBS biomolecular solvation software suite. Protein Science, 27(1), 112-128.
  • Kaldor, S. W., Kalish, V. J., Davies, J. F., Shetty, B. V., Fritz, J. E., Appelt, K., Burgess, J. A., Campanale, K. M., Chirgadze, N. Y., Clawson, D. K., Dressman, B. A., Hatch, S. D., Khalil, D. A., Kosa, M. B., Lubbehusen, P. P., Muesing, M. A., Patick, A. K., Reich, S. H., Su, K. S., & Tatlock, J. H. (1997). Viracept (nelfinavir mesylate, AG1343): A potent, orally bioavailable inhibitor of HIV-1 protease. Journal of Medicinal Chemistry, 40(24), 3979-3985.
  • Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., & Bolton, E. E. (2019). PubChem 2019 update: Improved access to chemical data. Nucleic Acids Research, 47(D1), D1102-D1109.
  • Kumar, D., Kumari, K., Vishvakarma, V. K., Jayaraj, A., Kumar, D., Ramappa, V. K., Patel, R., Kumar, V., Dass, S. K., Chandra, R., & Singh, P. (2020). Promising inhibitors of main protease of novel corona virus to prevent the spread of COVID-19 using docking and molecular dynamics simulation. Journal of Biomolecular Structure and Dynamics, 1-15.
  • Li, Z., Li, X., Huang, Y.-Y., Wu, Y., Liu, R., Zhou, L., Lin, Y., Wu, D., Zhang, L., Liu, H., Xu, X., Yu, K., Zhang, Y., Cui, J., Zhan, C.-G., Wang, X., & Luo, H.-B. (2020). Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs. Proceedings of the National Academy of Sciences, 117(44), 27381-27387.
  • Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson, A. J. (2009). AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. Journal of computational chemistry, 30(16), 2785-2791.
  • Rich, D. H., Sun, C. Q., Prasad, J. V. N. V., Pathiasseril, A., Toth, M. V., Marshall, G. R., Clare, M., Mueller, R. A., & Houseman, K. (1991). Effect of hydroxyl group configuration in hydroxyethylamine dipeptide isosteres on HIV protease inhibition. Evidence for multiple binding modes. Journal of Medicinal Chemistry, 34(3), 1222-1225.
  • Roberts, N. A., Martin, J. A., Kinchington, D., Broadhurst, A. V., Craig, J. C., Duncan, I. B., Galpin, S. A., Handa, B. K., Kay, J., & Kröhn, A. (1990). Rational design of peptide-based HIV proteinase inhibitors. Science (New York, N.Y.), 248(4953), 358-361.
  • Solis-Vasquez, L., Santos-Martins, D., Koch, A., & Forli, S. (2020). Evaluating the Energy Efficiency of OpenCL-accelerated AutoDock Molecular Docking. 2020 28th Euromicro International Conference on Parallel, Distributed and Network-Based Processing (PDP), 162-166.
  • Summa, V., Petrocchi, A., Bonelli, F., Crescenzi, B., Donghi, M., Ferrara, M., Fiore, F., Gardelli, C., Gonzalez Paz, O., Hazuda, D. J., Jones, P., Kinzel, O., Laufer, R., Monteagudo, E., Muraglia, E., Nizi, E., Orvieto, F., Pace, P., Pescatore, G., … Rowley, M. (2008). Discovery of Raltegravir, a Potent, Selective Orally Bioavailable HIV-Integrase Inhibitor for the Treatment of HIV-AIDS Infection. Journal of Medicinal Chemistry, 51(18), 5843-5855.
  • Wu, A., Peng, Y., Huang, B., Ding, X., Wang, X., Niu, P., Meng, J., Zhu, Z., Zhang, Z., Wang, J., Sheng, J., Quan, L., Xia, Z., Tan, W., Cheng, G., & Jiang, T. (2020). Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China. Cell Host & Microbe, 27(3), 325-328.
  • Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., & Hilgenfeld, R. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 368(6489), 409-412.
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Details

Primary Language Turkish
Subjects Engineering
Journal Section Articles
Authors

Gizem Tatar 0000-0001-6642-6870

Ercüment Yılmaz 0000-0002-3712-7086

Publication Date December 31, 2021
Published in Issue Year 2021 Issue: 32

Cite

APA Tatar, G., & Yılmaz, E. (2021). SARS-CoV-2 Ana Proteaz Enzimine Yönelik Antiviral Bileşiklerin Bilgisayar Destekli İlaç Tasarımı Yöntemleri ile Değerlendirilmesi. Avrupa Bilim Ve Teknoloji Dergisi(32), 1043-1047. https://doi.org/10.31590/ejosat.1041077