Gizem TATAR, Bedriye Seda KURŞUN AKTAR

388

Bazı Kalkonların COVID-19 Tedavisine Yönelik SARS-CoV-2 Ana Proteaza Bağlanma Mekanizmasının Moleküler Kenetleme Yaklaşımı ile Aydınlatılması

SARS-CoV-2’nin neden olduğu COVID-19 hastalığının bulaşma hızının ve ağır hastalık oluşturma potansiyelinin yüksek olması dolasıyla Dünya Sağlık Örgütü tarafından global bir pandemi olarak tanımlanmıştır. Günümüzde COVID-19 pandemisini önlemek amacıyla birçok ilaç çalışmaları yapılmakta olup ancak henüz tedavisine yönelik etkili ve güvenli bir ilaç mevcut değildir. Bu araştırmaların hızlı ve az maliyet ile klinik aşamalara geçmesi için SARS-CoV-2'in replikasyon ve transkripsiyon mekanizmasında etkili olan proteinlere karşı birçok bileşik bilgisayar destekli ilaç tasarımı yöntemleri ile taranmaktadır. Bu sayede, etkinliği deneysel çalışmalarla test edilmiş bileşiklerin SARS-CoV-2’e ait önemli yapısal proteinlerine yönelik etkinlikleri moleküler seviyede aydınlatılmaktadır. Bu çalışmada daha önce deneysel çalışmalar ile etkinliği belirlenmiş 32 adet kalkon türevli bileşiklerin moleküler kenetlenme yöntemi ile SARS-CoV-2 Main protease (Mpro) enzimine yönelik in siliko biyolojik etkinliği ve moleküler mekanizması incelenmiştir. Bu çalışma sonuçlarına göre, bileşik 5, 6, 14, 25 ve 32 hedef proteine ait referans bileşik (N3)’e göre SARS-CoV-2 Mpro'ya karşı daha iyi bağlanma afinitesi göstermişlerdir. Elde edilen bu veriler sonucunda, COVID-19 hastalığının tedavisine yönelik biyolojik etkinliği yüksek kimyasal bileşikler belirlenmiştir. Bu bilgiler, COVID-19 tedavisi için daha etkili antiviral ilaçların geliştirilmesi için yapılacak klinik çalışmalara rehberlik edecektir.

Elucidation of the Binding Mechanism of Several Chalcone Against SARS-CoV-2 Main Protease Enzyme for COVID-19 Treatment by Molecular Docking Approach

COVID-19 disease, which is cause by the SARS-CoV-2, has been defined as a global pandemic by the World Health Organization due to its high transmission rate and high potential to cause severe disease. Today, many drug studies are carried out to prevent the COVID-19 pandemic, but there is no effective and safe drug for its treatment yet. Many compounds are screened against proteins that are effective in the replication and transcription mechanism of SARS-CoV-2 by computer-aided drug design methods for proceeding to clinical stages with quick and low-cost. In this way, the activities of the compounds whose efficacy has been tested in experimental studies towards the important structural proteins of SARS-CoV-2 are illuminated at the molecular level. In this study, the in silico biological activity and molecular mechanism of 32 chalconederived compounds, whose efficacy was determined by experimental studies, was investigated by molecular docking method for the SARS-CoV-2 Main protease (Mpro) enzyme. According to the results of this study, the compounds 5, 6, 14, 25 and 32 showed better binding affinity for SARS-CoV-2 Mpro than the reference compound (N3) of the target protein. As a result, chemical compounds with potential biological activity have been identified for the treatment of COVID-19. This information will guide further clinical studies to develop more effective antiviral drugs for the treatment of COVID-19.
PDF

___

  • [1] Grifoni, A., Weiskopf, D. , (2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell, 181(7), 1489-1501.e15.
  • [2] Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi, Y., Ma, X., Zhan, F., Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., … Tan, W., (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. The Lancet, 395(10224), 565-574.
  • [3] 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.
  • [4] 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 M pro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289-293.
  • [5] 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.
  • [6] Banerjee, R., Perera, L., & Tillekeratne, L. M. V., (2021). Potential SARS-CoV-2 main protease inhibitors. Drug Discovery Today, 26(3), 804-816.
  • [7] Cui, W., Yang, K., & Yang, H., (2020). Recent Progress in the Drug Development Targeting SARS-CoV-Main Protease as Treatment for COVID-19. Frontiers in Molecular Biosciences, 7.
  • [8] 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.
  • [9] 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.
  • [10] Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K., & Hilgenfeld, R., (2020). Crystal structure of SARSCoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 368(6489), 409-412.
  • [11] Marquina, S., Maldonado-Santiago, M., SánchezCarranza, J. N., Antúnez-Mojica, M., GonzálezMaya, L., Razo-Hernández, R. S., & Alvarez, L., (2019). Design, synthesis and QSAR study of 2′- hydroxy-4′-alkoxy chalcone derivatives that exert cytotoxic activity by the mitochondrial apoptotic pathway. Bioorganic & Medicinal Chemistry, 27(1), 43-54.
  • [12] Bukhari, S. N. A., Butt, A. M., Amjad, M. W. B., Ahmad, W., Shah, V. H., & Trivedi, A. R., (2013). Synthesis and evaluation of chalcone analogues based pyrimidines as angiotensin converting enzyme inhibitors. Pakistan Journal of Biological Sciences: PJBS, 16(21), 1368-1372.
  • [13] Israf, D. A., Khaizurin, T. A., Syahida, A., Lajis, N. H., & Khozirah, S., (2007). Cardamonin inhibits COX and iNOS expression via inhibition of p65NF-kappaB nuclear translocation and IkappaB phosphorylation in RAW 264.7 macrophage cells. Molecular Immunology, 44(5), 673-679.
  • [14] Yamamoto, T., Yoshımura, M., Yamaguchı, F., Kouchı, T., Tsujı, R., Saıto, M., Obata, A., & Kıkuchı, M., (2004). Anti-allergic Activity of Naringenin Chalcone from a Tomato Skin Extract. Bioscience, Biotechnology, and Biochemistry, 68(8), 1706-1711.
  • [15] Aoki, N., Muko, M., Ohta, E., & Ohta, S., (2008). CGeranylated Chalcones from the Stems of Angelica keiskei with Superoxide-Scavenging Activity. Journal of Natural Products, 71(7), 1308-1310.
  • [16] Abdullah, M. I., Mahmood, A., Madni, M., Masood, S., & Kashif, M., (2014). Synthesis, characterization, theoretical, anti-bacterial and molecular docking studies of quinoline based chalcones as a DNA gyrase inhibitor. Bioorganic Chemistry, 54, 31-37.
  • [17] Kurşun-Aktar, B. S., Sıcak, Y., Tok Taşkın, T., Oruç-Emre, E. E., Şahin-Yağlıoğlu, A., Karaküçük-İyidoğan, A., Öztürk, M., Demirtaş, İ., (2020). Designing heterocyclic chalcones, benzoyl/sulfonyl hydrazones: An insight into their biological activities and molecular docking study. Journal of Molecular Structure, 1211, 128059.
  • [18] Kurşun Aktar, B. S., Oruç-Emre, E. E., Demı̇ rtaş, İ., Yağlioğlu, A. Ş., İyı̇ doğan, A. K., Güler, Ç., & Adem, Ş., (2018). Synthesis and biological evaluation of novel chalcones bearing morpholine moiety as antiproliferative agents. Turkısh Journal Of Chemıstry, 42(2), 482-492.
  • [19] Elkhalifa, D., Al-Hashimi, I., Al Moustafa, A.-E., & Khalil, A., (2021). A comprehensive review on the antiviral activities of chalcones. Journal of Drug Targeting, 29(4), 403-419.
  • [20] Jo, S., Kim, S., Shin, D. H., & Kim, M.-S., (2020). Inhibition of SARS-CoV 3CL protease by flavonoids. Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), 145-151.
  • [21] Solnier, J., & Fladerer, J.-P., (2020). Flavonoids: A complementary approach to conventional therapy of COVID-19? Phytochemistry Reviews, 1-23.
  • [22] Tatar, G., Salmanli, M., Dogru, Y., & Tuzuner, T., (2021). Evaluation of the effects of chlorhexidine and several flavonoids as antiviral purposes on SARS-CoV-2 main protease: Molecular docking, molecular dynamics simulation studies. Journal of Biomolecular Structure and Dynamics, 1-10.
  • [23] Kurşun-Aktar, B. S., Oruç-Emre, E. E., Karaküçükİyı̇ doğan, A., Yağlioğlu, A. Ş., Demı̇ rtaş, İ., & Tekı̇ n, Ş., (2017). Synthesis and structure-activity relationship study: Anticancer chalcones derived from 4′-morpholinoacetophenone. Marmara Pharmaceutical Journal, 21(4), 949-960.
  • [24] Kurşun Aktar, B. S., Oruç-Emre, E. E., Demirtaş, I., Yaglioglu, A. S., Guler, C., Adem, S., & Karaküçük Iyidoğan, A., (2017). Synthesis of novel fluorinated chalcones derived from 4′- morpholinoacetophenone and their antiproliferative effects. Journal of Molecular Structure, 1149, 632-639.
  • [25] Ambinter, Search and Inquire chemicals online www.ambinter.com
  • [26] Khalil, O. M., (2011). Synthesis of some chalcones and pyrazolines carrying morpholinophenyl moiety as potential anti-inflammatory agents. Archiv Der Pharmazie, 344(4), 242-247.
  • [27] Marshall, G. R., (1987). Computer-Aided Drug Design. Annual Review of Pharmacology and Toxicology, 27(1), 193-213.
  • [28] 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: A Publication of the Protein Society, 27(1), 112-128.
  • [29] Dassault Systèmes BIOVIA. Discovery Studio Modeling Environment, Release 2020. San Diego: Dassault Systèmes; 2020)
  • [30] 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.
  • [31] Daina, A., Michielin, O., & Zoete, V., (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 42717.
  • [32] Ullrich, S., & Nitsche, C., (2020). The SARS-CoV2 main protease as drug target. Bioorganic & Medicinal Chemistry Letters, 30(17), 127377.
  • [33] Sıcak, Y., (2021) Design and Antiproliferative and Antioxidant Activities of Furan-Based Thiosemicarbazides and 1, 2, 4-Triazoles: Their Structure-Activity Relationship and SwissADME Predictions’’ . Medicinal Chemistry Research, 30(8), 1557-1568.
International journal of advances in engineering and pure sciences (Online)-Cover
  • Yayın Aralığı: Yılda 4 Sayı
  • Yayıncı: Marmara Üniversitesi
Arşiv
Sayıdaki Diğer Makaleler

Escherichia coli'de MMLV Ters Transkriptaz Enziminin Yüksek Düzeyde Üretimi

İsa GÖKÇE, Özlem KAPLAN, Rizvan İMAMOĞLU

Bazı Kalkonların COVID-19 Tedavisine Yönelik SARS-CoV-2 Ana Proteaza Bağlanma Mekanizmasının Moleküler Kenetleme Yaklaşımı ile Aydınlatılması

Gizem TATAR, Bedriye Seda KURŞUN AKTAR