RNA-DEPENDENT RNA POLYMERASE (RDRP) INHIBITOR DRUGS AGAINST SARS-COV-2: A MOLECULAR DOCKING STUDY

Yıl 2022, Cilt: 46 Sayı: 1, 62 - 77, 29.01.2022

Sarah Gado Zeynep Alagöz

https://doi.org/10.33483/jfpau.963384

Cited By: 1

Öz

Objective: SARS-CoV-2 associated viral pandemic was first reported in Wuhan, China, in December 2019. Due to the rapid increase in its pathogenicity, SARS-CoV-2 was declared a global pandemic by WHO on March 11, 2020. For that reason, determining the most attractive viral protein targets became a must. One of the most important target proteins is SARS-COV-2 RNA-dependent RNA polymerase (RdRp) on which COVID-19 depends in its replication process. This study aimed to examine the possible interactions between RdRp and the most promising RdRp nucleoside inhibitors especially Purine nucleoside analogs, to detect the most important residues that commonly interact with RdRp's inhibitors and to investigate whether if there any mutations have been observed so far in these residues or not.
Material and Method: Molecular docking studies were carried out using AutoDock Vina between SARS-CoV-2 RdRp and drugs approved against different viral RdRps (Galidesivir, Remdesivir, Ribavirin, Sofosbuvir, and Favipiravir) as well as physiological nucleotides (ATP and GTP). Based on the obtained results, a detailed surface-interaction analysis was also performed using Pymol and Discovery Studio Visualizer software for the models that exhibited the most suitable location and configuration in space.
Result and Discussion: All the tested molecules were able to bind to SARS-CoV-2 RdRp successfully. Also, they all commonly interact with 9 different amino acids (Arg553, Arg555, Asp618, Asp623, Ser682, Asn691, Ser759, Asp760, and Asp761), and 3 different Template-primer RNA nucleotides (U10, A11, and U20) causing inhibition of viral RdRp via non obligate RNA chain termination.

Anahtar Kelimeler

COVID-19, molecular docking, RdRp, nucleotide analogs

SARS-COV-2'YE KARŞI RNA-BAĞIMLI RNA POLİMERAZ (RDRP) İNHİBİTÖR İLAÇLARI: BİR MOLEKÜLER DOCKİNG ÇALIŞMASI

Öz

Amaç: SARS-CoV-2 ile ilişkili viral pandemisi ilk olarak Aralık 2019'da Çin'in Wuhan kentinde bildirilmiştir. enfeksiyon gücünün yüksek olması nedeniyle, Dünya Sağlık Örgütü (DSÖ) 11 Mart 2020 tarihinde SARS-CoV-2’yi küresel pandemi olarak ilan etmiştir. Bu nedenle en önemli viral protein hedeflerinin belirlenmesi bir zorunluluk haline geldi. En önemli hedef proteinlerden biri ise, SARS-COV-2’nin replikasyon sürecinin bağlı olduğu RNA'ya bağımlı RNA polimerazdır (RdRp). Bu çalışmada RdRp ile RdRp nükleozit inhibitörleri, özellikle de Purin nükleozid analogları arasındaki olası etkileşimlerin incelenmesi, RdRp inhibitörleri ile yaygın olarak etkileşime giren en önemli kalıntıların saptanması ve bu kalıntılarda şimdiye kadar herhangi bir mutasyon gözlemlenip gözlemlenmediği araştırılması amaçlanmıştır.
Gereç ve Yöntem: SARS-CoV-2 RdRp’ye karşı fizyolojik nükleotidler (ATP ve GTP) ve farklı viral RdRpler’e karşı onaylanmış ilaçlar (Galidesivir, Remdesivir, Ribavirin, Sofosbuvir ve Favipiravir) olmak üzere toplam 7 bileşik test edilmiştir. RdRp ile bu 7 bileşik arasında AutoDock Vina yardımıyla moleküler docking çalışmaları gerçekleştirilmiş olup moleküler docking çalışmalarından elde edilen sonuçlara ve uzaydaki konfigürasyonlarına göre en uygun olan modelleri için de detaylı yüzey etkileşim analizi Pymol ve Discovery Studio Visualizer software yardımıyla yapılmıştır.
Sonuç ve Tartışma: Test edilen tüm moleküller, SARS-CoV-2 RdRp'ye başarıyla bağlanabilmiştir. Ayrıca hepsi 9 farklı amino asit ile (Arg553, Arg555, Asp618, Asp623, Ser682, Asn691, Ser759, Asp760 ve Asp761) aynı zamanda 3 farklı Template-primer RNA nükleotidi (U10, A11 ve U20) ile etkileşime girmiş ve zorunlu olmayan RNA zinciri sonlandırması yoluyla viral RdRp'nin inhibisyonuna neden olmuşlardır.

Anahtar Kelimeler

COVID-19, moleküler docking, RdRp, nükleotid analogları

Kaynakça

• 1. Lai,C.C., Shih, T.P., Ko, W.C., Tang, H.J., Hsueh, P.R. (2020). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. International Journal of Antimicrobial Agents, 55(3), 105924 2. Qu, J., Cao, B. & Chen, R. (2020). Covid-19 the essentials of prevention and treatment. Elsevier Science, p. 1-3
• 3. Pal M, Berhanu G, Desalegn C, Kandi, V. (2020) Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): An update. Cureus, 12(3): e7423. doi:10.7759/cureus.7423
• 4. Zhu, G., Zhu, C., Zhu, Y. & Sun, F. (2020). Minireview of progress in the structural study of SARS-CoV-2 proteins. Current Research in Microbial Sciences, 1, 53-61.
• 5. Rasool, N., Yasmin, F., Sahai, S., Hussain, W., Inam, H., & Arshad, A. (2021). Biological perspective of thiazolide derivatives against Mpro and MTase of SARS-CoV-2: Molecular docking, DFT and MD simulation investigations. Chemical Physics Letters, 771, 138463.
• 6. Ren, B. (2020). The AI-discovered aetiology of COVID-19 and rationale of the irinotecan+ etoposide combination therapy for critically ill COVID-19 patients. Medical Hypotheses, 144, 110385
• 7. Boopathi, S., Poma, A. & Kolandaivel, P. (2020). Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment. Journal of Biomolecular Structure and Dynamics, 39(9), 3409-3418.
• 8. Zhu, W., Chen, C., Gorshkov, K., Xu, M., Lo, D.& Zheng, W. (2020). RNA-dependent RNA polymerase as a target for covıd-19 drug discovery. Slas Dıscovery: Advancing The Science Of Drug Discovery, 25(10),1141-1151.
• 9. Demir-Tekol, S. (2020). SARS-CoV-2: Virolojisi ve tanıda kullanılan mikrobiyolojik testler. Southern Clinics of Istanbul Eurasia, 1(1), 8-12
• 10. Cheng, Y., Chao, T., Li, C., Chiu, M., Kao, H., Wang, S., Pang, Y., Lin, C., Tsai, Y., Lee, W., Tao, M., Ho, T., Wu, P., Jang, L., Chen, P., Chang, S., Yeh, S. (2020). Furin ınhibitors block SARS-COV-2 spike protein cleavage to suppress virus production and cytopathic effects. Cell Reports, 33(2), 108254.
• 11. Gao, Y., Yan, L., Huang, Y., Liu, F., Zhao, Y., Cao, L. & Wang, T. (2020). Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, 368(6492), 779-782.
• 12. Yin, W., Mao, C., Luan, X., Shen, D., Shen, Q., Su, H., Wang, X., Zhou, F., Zhao, W., Gao, M., Chang, S., Xie, Y., Tian, G., Jiang, H., Tao, S., Shen, J., Jiang, Y., Jiang, H., Xu, Y., Zhang, S., Zhang, Y.& Xu, H. (2020). Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science, 368(6498), 1499-1504.
• 13. Kirchdoerfer, R. N., Ward, A. B. (2019). Structure of the SARS-CoV nsp12 polymerase bound to nsp7 and nsp8 co-factors. Nature Communications,10, 2342.
• 14. Faheem, Kumar, B., Sekhar, K., Kunjiappan, S., Jamalis, J., Balaña-Fouce, R., Tekwani, B., & Sankaranarayanan, M. (2020). Druggable targets of SARS-CoV-2 and treatment opportunities for COVID-19. Bioorganic Chemistry, 104, 104269.
• 15. Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., & Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 30, 269–271.
• 16. Eastman, R., Roth, J., Brimacombe, K., Simeonov, A., Shen, M., Patnaik, S., & Hall, M. (2020). Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19. ACS Central Science, 6, 672–683.
• 17. Du, Y., & Chen, X. (2020). Favipiravir: Pharmacokinetics and concerns about clinical trials for 2019‐nCoV infection. Clinical Pharmacology and Therapeutics, 108(2), 242-247
• 18. Helen S Te, Randall, G., & Jensen, D. (2007). Mechanism of action of ribavirin in the treatment of chronic hepatitis C. Gastroenterol and Hepatol, 3(3), 218-225.
• 19. Gong, W., Zhou, T., Wu, S., Ye, J., Xu, J., Zeng, F., Su, Y., Han, Y., Lv, Y., Zhang, Y., & Cai, X. (2021). A retrospective analysis of clinical efficacy of ribavirin in adults hospitalized with severe COVID-19. Journal of Infection and Chemotherapy Home, 27(6), 876-881
• 20. Padhi, A., Shukla, R., Saudagar, P., & Tripathi, T. (2021). High-throughput rational design of the Remdesivir binding site in the RdRp of SARS-CoV-2: implications for potential resistance. iScience, 24(1), 101992.
• 21. Pardo, J., Shukla, A., Chamarthi, G., & Gupte, A. (2020). The journey of remdesivir: from Ebola to COVID-19. Drugs in Context, 9, 1-9.
• 22. Beigel, J., Tomashek, K., Dodd, L., Mehta, A., Zingman, B., Kalil, A., Hohmann, E., Chu, H., Luetkemeyer, A., …. Kline, S. (2020). Remdesivir for the treatment of Covid-19 — Final report. The New England Journal of Medicine, 383, 1813-1826
• 23. Tiwari, V., Beer, J., Sankaranarayanan, N., Swanson-Mungerson, M., Desai, U. (2020). Discovering small-molecule therapeutics against SARS-CoV-2. Drug Discovery Today, 25(8), 1535-1544.
• 24. Gordon, C., Tchesnokov, E., Woolner, E., Feng, J., Porter, D., & Götte, M. (2020). Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. Journal of Biological Chemistry, 295(20), 6785-6797.