Moleküler Bağlama Yaklaşımı Kullanılarak Olası Maymun Çiçeği Salgını İçin İlaç Yeniden Konumlandırma Stratejisi

Abstract

Bu çalışmada, maymun çiçeği virüsü için ilaç yeniden konumlandırma stratejisi, moleküler bağlama (docking) ve moleküler dinamik (MD) simülasyon yaklaşımları kullanılarak gerçekleştirilmiştir. Bu amaçla, klinik tedavide diğer hastalıklar için halihazırda onaylanmış olan olası ilaçlar taranmıştır. Potansiyel ilaç adayları, AutoDock yazılımı kullanılarak iki grupta analiz edilmiştir: 1) DNA polimeraz inhibitörleri ve 2) RNA polimeraz inhibitörleri. Moleküler bağlama araştırmaları, maymun çiçeği enfeksiyonuna karşı etkili olabilecek toplam yedi olası ilaç adayı belirlemiştir: beşi DNA polimeraz inhibitörü ve ikisi RNA polimeraz inhibitörüdür. Ayrıca, moleküler dinamik simülasyon sonuçları, bahsedilen inhibitörlerin güçlü ilaç adayları olabileceğini doğrulamıştır. Bu aday ilaçlardan etravirine (-8,04 Kcal/mol) ve valasiklovir (-7,57 Kcal/mol), ASP347 ve ASP462 kalıntılarının aktif bölgesinde enzime karşı daha yüksek bağlanma afinitesi göstermiştir. Bunun yanı sıra, emetin dihidroklorürün, maymun çiçeği virüsünün RNA polimeraz inhibitörü olarak en güçlü ilaç adayı olduğu ve enzimin katalitik bölgesine -7,17 Kcal/mol bağlanma enerjisi ile bağlandığı gözlemlenmiştir. Bu çalışma sonucunda, oldukça etkili bir DNA polimeraz inhibitörü olarak etravirine ve bir RNA polimeraz inhibitörü olarak emetin dihidroklorür, maymun çiçeği tedavisi için potansiyel ilaç adayları olarak önerilmektedir. Bu ilaçlar daha önce ABD Gıda ve İlaç Dairesi (FDA) tarafından diğer viral enfeksiyonlar için onaylandığından, uzun güvenlik protokollerine ve yüksek geliştirme maliyetlerine gerek kalmadan maymun çiçeği enfeksiyonu etkili bir şekilde kontrol altına alınabilir.

Keywords

• monkeypox virus;
• antiviral
• etravirine
• molecular docking
• molecular dynamics simulation;
• drug repurposing

Computational Identification of Potential Antiviral Agents Against Monkeypox Virus

Abstract

This study introduces a drug repurposing approach for monkeypox virus using molecular docking and molecular dynamics (MD) simulations to screen clinically approved drugs for other diseases. Potential candidates were analyzed with AutoDock software in two categories: (1) DNA polymerase inhibitors and (2) RNA polymerase inhibitors. Docking analysis identified seven promising compounds—five DNA polymerase and two RNA polymerase inhibitors—showing strong affinity toward monkeypox targets. MD simulations further confirmed their binding stability. Among them, etravirine (−8.04 kcal/mol) and valaciclovir (−7.57 kcal/mol) exhibited the highest affinity to DNA polymerase active sites at residues ASP347 and ASP462. Moreover, emetine dihydrochloride (−7.17 kcal/mol) demonstrated the strongest binding to the catalytic site of RNA polymerase. Consequently, etravirine and emetine dihydrochloride are proposed as potential therapeutics against monkeypox. Since these compounds are already approved by the U.S. Food and Drug Administration (FDA) for other viral infections, extensive safety testing and high development costs can be avoided, making this repurposing strategy an efficient and cost-effective option for managing monkeypox infection.

Keywords

• Monkeypox Virus
• Etravirine
• Molecular Docking
• Molecular Dynamics Simulation
• Drug Repurposing

References

1. Adalja, A., & Inglesby, T. (2019). Broad-spectrum antiviral agents: a crucial pandemic tool. Expert Review of Anti-Infective Therapy, 17(7), 467-470. https://doi.org/10.1080/14787210.2019.1635009
2. Adler, H., Gould, S., Hine, P., Snell, L. B., Wong, W., Houlihan, C. F., Osborne, J. C., Rampling, T., Beadsworth, M. B. J., Duncan, C. J. A., Dunning, J., Fletcher, T. E., Hunter, E. R., Jacobs, M., Khoo, S. H., Newsholme, W., Porter, D., Porter, R. J., Ratcliffe, L., … Price, N. M. (2022). Clinical features and management of human monkeypox: A retrospective observational study in the UK. The Lancet Infectious Diseases, 22(8), 1153-1162. https://doi.org/10.1016/S1473-3099(22)00228-6
3. Akinboye, E. S., & Bakare, O. (2011). Biological activities of emetine. The Open Natural Products Journal, 411(8), 8-15. https://doi.org/10.2174/1874848101104010008
4. Amani, A., York, P., de Waard, H., & Anwar, J. (2011). Molecular dynamics simulation of a polysorbate 80 micelle in water. Soft Matter, 7(6), 2900-2908. https://doi.org/10.1039/C0SM00965B
5. Arslan, M. E., Türkez, H., Sevim, Y., Selvitopi, H., Kadi, A., Öner, S., & Mardinoğlu, A. (2023). Costunolide and parthenolide ameliorate MPP+ induced apoptosis in the cellular Parkinson’s disease model. Cells, 12(7), Article 992. https://doi.org/10.3390/cells12070992
6. Ashburn, T. T., & Thor, K. B. (2004). Drug repositioning: Identifying and developing new uses for existing drugs. Nature Reviews Drug Discovery, 3, 673-683. https://doi.org/10.1038/nrd1468
7. Aswathy, S. V., Joe, I. H., Rameshkumar, K. B., & Ibrahim, J. M. (2024). Insights into the role of RAHB and IHB interactions for the structure-activity relationship of caged xanthone morellic acid: Spectroscopic and DFT exploration, molecular docking, and molecular dynamics simulation studies as an antituberculosis agent. Journal of Molecular Structure, 1303(1), Article 137429. https://doi.org/10.1016/j.molstruc.2023.137429
8. Boroujeni, M. B., Dastjerdeh, M. S., Shokrgozar, M., Rahimi, H., & Omidinia, E. (2021). Computational driven molecular dynamics simulation of keratinocyte growth factor behavior at different pH conditions. Informatics in Medicine Unlocked, 23(1), Article 100514. https://doi.org/10.1016/j.imu.2021.100514

9. Breckenridge, A., & Jacob, R. (2019). Overcoming the legal and regulatory barriers to drug repurposing. Nature Reviews Drug Discovery, 18, 1-2. https://doi.org/10.1038/nrd.2018.92
10. Brown, K., & Leggat, P. (2016). Human monkeypox: Current state of knowledge and implications for the future. Tropical Medicine and Infectious Disease, 1(1), Article 8. https://doi.org/10.3390/tropicalmed1010008
11. Bunge, E. M., Hoet, B., Chen, L., Lienert, F., Weidenthaler, H., Baer, L. R., & Steffen, R. (2022). The changing epidemiology of human monkeypox—A potential threat? A systematic review. PLoS Neglected Tropical Diseases, 16(2), Article e0010141. https://doi.org/10.1371/journal.pntd.0010141
12. Caufriez, A., Tabernilla, A., Van Campenhout, R., Cooreman, A., Leroy, K., Sanz Serrano, J., Kadam, P., dos Santos Rodrigues, B., Lamouroux, A., Ballet, S., & Vinken, M. (2022). Effects of drugs formerly suggested for COVID-19 repurposing on pannexin1 channels. International Journal of Molecular Sciences, 23(10), Article 5664. https://doi.org/10.3390/ijms23105664
13. Chen, G., Seukep, A. J., & Guo, M. (2020). Recent advances in molecular docking for the research and discovery of potential marine drugs. Marine Drugs, 18(11), Article 545. https://doi.org/10.3390/md18110545
14. Chiang, A. P., & Butte, A. J. (2009). Systematic evaluation of drug–disease relationships to identify leads for novel drug uses. Clinical Pharmacology & Therapeutics, 86(5), 507-510. https://doi.org/10.1038/clpt.2009.103
15. Choy, K. T., Wong, A. Y. L., Kaewpreedee, P., Sia, S. F., Chen, D., Hui, K. P. Y., Chu, D. K. W., Chan, M. C. W., Cheung, P. P. H., Huang, X., Peiris, M., & Yen, H. L. (2020). Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Research, 178, Article 104786. https://doi.org/10.1016/j.antiviral.2020.104786
16. Colis, L., Ernst, G., Sanders, S., Liu, H., Sirajuddin, P., Peltonen, K., DePasquale, M., Barrow, J. C., & Laiho, M. (2014). Design, synthesis, and structure–activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors. Journal of Medicinal Chemistry, 57(11), 4950-4961. https://doi.org/10.1021/jm5004842
17. Croxtall, J. D. (2012). Etravirine: A review of its use in the management of treatment-experienced patients with HIV-1 infection. Drugs, 72(6), 847-869. https://doi.org/10.2165/11209110-000000000-00000
18. Damon, I. K. (2011). Status of human monkeypox: Clinical disease, epidemiology and research. Vaccine, 29 (Suppl 4), D54-D59. https://doi.org/10.1016/j.vaccine.2011.04.014
19. Fadlalla, M., Ahmed, M., Ali, M., Elshiekh, A. A., & Yousef, B. A. (2022). Molecular docking as a potential approach in repurposing drugs against COVID-19: A systematic review and novel pharmacophore models. Current Pharmacology Reports, 8(3), 212-226. https://doi.org/10.1007/s40495-022-00285-w
20. Fife, K. H., Barbarash, R. A., Rudolph, T., Degregorio, B., Roth, R., & Valaciclovir International Herpes Simplex Virus Study Group (1997). Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection: results of an international, multicenter, double-blind, randomized clinical trial. Sexually Transmitted Diseases, 24(8), 481-486. https://doi.org/10.1097/00007435-199709000-00007
21. Gouleni, N., Di Rienzo, A., Yılmaz, A., Selvitopi, H., Arslan, M. E., Mardinoglu, A., Turkez, H., Di Stefano, A., Vassiliou, S., & Cacciatore, I. (2023). Novel styryl-thiazole hybrids as potential anti-Alzheimer's agents. RSC Medicinal Chemistry, 14(11), 2315-2326. https://doi.org/10.1039/d3md00308f
22. Grimm, C., Hillen, H. S., Bedenk, K., Bartuli, J., Neyer, S., Zhang, Q., Hüttenhofer, A., Erlacher, M., Dienemann, C., Schlosser, A., Urlaub, H., Böttcher, B., Szalay, A. A., Cramer, P., & Fischer, U. (2019). Structural basis of poxvirus transcription: Vaccinia RNA polymerase complexes. Cell, 179(7), 1537-1550.e19. https://doi.org/10.1016/j.cell.2019.11.024
23. Halder, D., Das, S., Joseph, A., & Jeyaprakash, R. S. (2023). Molecular docking and dynamics approach to in silico drug repurposing for inflammatory bowel disease by targeting TNF alpha. Journal of Biomolecular Structure and Dynamics, 41(8), 3462-3475. https://doi.org/10.1080/07391102.2022.2050948
24. Hansson, T., Oostenbrink, C., & van Gunsteren, W.F.V. (2002). Molecular dynamics simulations. Current Opinion in Structural Biology, 12(2), 190-196. https://doi.org/10.1016/S0959-440X(02)00308-1
25. Hegde, R. N., Parashuraman, S., Iorio, F., Ciciriello, F., Capuani, F., Carissimo, A., Carrella, D., Belcastro V., Subramanian, A., Bounti, L., Persico, M., Carlile, G., Galietta, L., Thomas, D. Y., Di Bernardo, D., & Luini, A. (2015). Unravelling druggable signalling networks that control F508del-CFTR proteostasis. eLife, 4, Article e10365. https://doi.org/10.7554/elife.10365
26. Honkoop, P., & de Man, R. A. (2003). Entecavir: A potent new antiviral drug for hepatitis B. Expert Opinion on Investigational Drugs, 12(4), 683-688. https://doi.org/10.1517/13543784.12.4.683
27. Hutin, Y. J., Williams, R. J., Malfait, P., Pebody, R., Loparev, V. N., Ropp, S. L., Rodriguez, M., Knight, J. C., Tshioko, F. K., Khan, A. S., Szczeniowski, M. V., & Esposito, J. J. (2001). Outbreak of human monkeypox, Democratic Republic of Congo, 1996 to 1997. Emerging Infectious Diseases, 7(3), 434-438. https://doi.org/10.3201/eid0703.017311
28. Iorio, F., Isacchi, A., Di Bernardo, D., & Brunetti-Pierri, N. (2010). Identification of small molecules enhancing autophagic function from drug network analysis. Autophagy, 6(8), 1204-1205. https://doi.org/10.4161/auto.6.8.13551
29. Jacobs, R. Q., Huffines, A. K., Laiho, M., & Schneider, D. A. (2022). The small-molecule BMH-21 directly inhibits transcription elongation and DNA occupancy of RNA polymerase I in vivo and in vitro. Journal of Biological Chemistry, 298(1), Article 101450. https://doi.org/10.1016/j.jbc.2021.101450
30. Jalalvand, A., Khatouni, S. B., Najafi, Z. B., Fatahinia, F., Ismailzadeh, N., & Farahmand, B. (2022). Computational drug repurposing study of antiviral drugs against main protease, RNA polymerase, and spike proteins of SARS-CoV-2 using molecular docking method. Journal of Basic and Clinical Physiology and Pharmacology, 33(1), 85-95. https://doi.org/10.1515/jbcpp-2020-0369
31. Jayaram, B., Singh, T., Mukherjee, G., Mathur, A., Shekhar, S., & Shekhar, V. (2012). Sanjeevini: A freely accessible web-server for target directed lead molecule discovery. BMC Bioinformatics, 13 (Suppl 17), S7. https://doi.org/10.1186/1471-2105-13-S17-S7
32. Kao, A. (2003). Diagnosis and management of smallpox. AMA Journal of Ethics, 5(2), 51-53. https://doi.org/10.1001/virtualmentor.2003.5.2.cprl1-0302
33. Kast, R. E., Alfieri, A., Assi, H. I., Burns, T. C., Elyamany, A. M., Gonzalez-Cao, M., Karpel-Massler, G., Marosi, C., Salacz, M. E., Sardi, I., Van Vlierberghe, P., Zaghloul, M. S., & Halatsch, M. E. (2022). Mdact: A new principle of adjunctive cancer treatment using combinations of multiple repurposed drugs, with an example regimen. Cancers, 14(10), Article 2563. https://doi.org/10.3390/cancers14102563
34. Khandelwal, N., Chander, Y., Rawat, K. D., Riyesh, T., Nishanth, C., Sharma, S., Jindal, N., Tripathi, B. N., Barua, S., & Kumar, N. (2017). Emetine inhibits replication of RNA and DNA viruses without generating drug-resistant virus variants. Antiviral Research, 144, 196-204. https://doi.org/10.1016/j.antiviral.2017.06.006
35. Kleymann, G. (2004). Discovery, SAR and medicinal chemistry of herpesvirus helicase primase inhibitors. Current Medicinal Chemistry-Anti-Infective Agents, 3(1), 69-83. https://doi.org/10.2174/1568012043354242
36. Kumar, S., Kovalenko, S., Bhardwaj, S., Sethi, A., Gorobets, N. Y., Desenko, S. M., & Rathi, B. (2022). Drug repurposing against SARS-CoV-2 using computational approaches. Drug Discovery Today, 27(7), 2015-2027. https://doi.org/10.1016/j.drudis.2022.02.004
37. Laskowski, R. A., & Swindells, M. B. (2011). LigPlot+: Multiple ligand–protein interaction diagrams for drug discovery. Journal of Chemical Information and Modeling, 51(10), 2778-2786. https://doi.org/10.1021/ci200227u
38. Laube, I., Boehler, A., Renner, E. L., & Speich, R. (2004). Valaciclovir for chronic hepatitis B virus infection after lung transplantation. Infection, 32(1), 51-53. https://doi.org/10.1007/s15010-003-3094-5
39. Lazniewski, M., Dermawan, D., Hidayat, S., Muchtaridi, M., Dawson, W. K., & Plewczynski, D. (2022). Drug repurposing for identification of potential spike inhibitors for SARS-CoV-2 using molecular docking and molecular dynamics simulations. Methods, 203, 498-510. https://doi.org/10.1016/j.ymeth.2022.02.004
40. Likos, A. M., Sammons, S. A., Olson, V. A., Frace, A. M., Li, Y., Olsen-Rasmussen, M., Davidson, W., Galloway, R., Khristova, M. L., Reynolds, M. G., Zhao, H., Carroll, D. S., Curns, A., Formenty, P., Esposito, J. J., Regnery, R. L., & Damon, I. K. (2005). A tale of two clades: Monkeypox viruses. Journal of General Virology, 86(10), 2661-2672. https://doi.org/10.1099/vir.0.81215-0
41. MacDougall, C., & Guglielmo, B. J. (2004). Pharmacokinetics of valaciclovir. Journal of Antimicrobial Chemotherapy, 53(6), 899-901. https://doi.org/10.1093/jac/dkh244
42. Martínez, L. (2015). Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. PLOS ONE, 10(3), e0119264. https://doi.org/10.1371/journal.pone.0119264
43. Mazzucco, C. E., Hamatake, R. K., Colonno, R. J., & Tenney, D. J. (2008). Entecavir for treatment of hepatitis B virus displays no in vitro mitochondrial toxicity or DNA polymerase gamma inhibition. Antimicrobial Agents and Chemotherapy, 52(2), 598-605. https://doi.org/10.1128/aac.01122-07
44. McCollum, A. M., & Damon, I. K. (2014). Human monkeypox. Clinical Infectious Diseases, 58(2), 260-267. https://doi.org/10.1093/cid/ciu196
45. Meng, X. Y., Zhang, H. X., Mezei, M., & Cui, M. (2011). Molecular docking: A powerful approach for structure-based drug discovery. Current Computer-Aided Drug Design, 7(2), 146-157. https://doi.org/10.2174/157340911795677602
46. Michaelis, M., Langer, K., Vogel, J. U., Kreuter, J., Rabenau, H., Doerr, H. W., & Cinatl, J. (2002). In vitro antiviral activity of aphidicolin and its derivates. Arzneimittelforschung, 52(5), 393-399. https://doi.org/10.1055/s-0031-1299904
47. Moss, B. (1991). Vaccinia virus: A tool for research and vaccine development. Science, 252(5013), 1662-1667. https://doi.org/10.1126/science.2047875
48. Nakoune, E., & Olliaro, P. (2022). Waking up to monkeypox. BMJ, 377, Article o1321. https://doi.org/10.1136/bmj.o1321
49. Neff, J. M., Lane, J. M., Fulginiti, V. A., & Henderson, D. A. (2002). Contact vaccinia—transmission of vaccinia from smallpox vaccination. JAMA, 288(15), 1901-1905. https://doi.org/10.1001/jama.288.15.1901
50. Normand, C., Fortier, C., Thieulent, C., Marcillaud-Pitel, C., Pronost, S., & Hue, E. (2021, September). In vitro evaluation of nine antiviral compounds for their potential effect against equid herpesvirus-4. In Proceedings of the 11th International Equine Infectious Diseases Conference, 53(S56), Article 60. https://doi.org/10.1111/evj.89_13495
51. Okyay, R. A., Bayrak, E., Kaya, E., Şahin, A. R., Koçyiğit, B. F., Taşdoğan, A. M., Avcı, A., & Sümbül, H. E. (2022). Another epidemic in the shadow of COVID-19 pandemic: A review of monkeypox. Eurasian Journal of Medical Oncology, 6(2), 95-99. https://doi.org/10.14744/ejmo.2022.2022
52. Ozdemir, E. S., Le, H. H., Yildirim, A., & Ranganathan, S. V. (2022). In silico screening and testing of FDA-approved small molecules to block SARS-CoV-2 entry to the host cell by inhibiting spike protein cleavage. Viruses, 14(6), Article 1129. https://doi.org/10.3390/v14061129
53. Pagadala, N. S., Syed, K., & Tuszynski, J. (2017). Software for molecular docking: A review. Biophysical Reviews, 9(2), 91-102. https://doi.org/10.1007/s12551-016-0247-1
54. Pammolli, F., Magazzini, L., & Riccaboni, M. (2011). The productivity crisis in pharmaceutical R&D. Nature Reviews Drug Discovery, 10, 428-438. https://doi.org/10.1038/nrd3405
55. Pedrali-Noy, G., & Spadari, S. (1979). Effect of aphidicolin on viral and human DNA polymerases. Biochemical and Biophysical Research Communications, 88(4), 1194-1202. https://doi.org/10.1016/0006-291X(79)91106-9
56. Peltonen, K., Colis, L., Liu, H., Trivedi, R., Moubarek, M. S., Moore, H. M., Bai, B., Rudek, M. A., Bieberich, C. J., & Laiho, M. (2014). A targeting modality for destruction of RNA polymerase I that possesses anticancer activity. Cancer Cell, 25(1), 77-90. https://doi.org/10.1016/j.ccr.2013.12.009
57. Petersen, E., Abubakar, I., Ihekweazu, C., Heymann, D., Ntoumi, F., Blumberg, L., Asogun, D., Mukonka, V., Lule, S. A., Bates, M., Honeyborne, I., Mfinanga, S., Mwaba, P., Dar, O., Vairo, F., Mukhtar, M., Kock, R., McHugh, T. D., Ippolito, G., & Zumla, A. (2019). Monkeypox—Enhancing public health preparedness for an emerging lethal human zoonotic epidemic threat in the wake of the smallpox post-eradication era. International Journal of Infectious Diseases, 78, 78-84. https://doi.org/10.1016/j.ijid.2018.11.008
58. Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., Doig, A., Guilliams, T., Latimer, J., McNamee, C., Norris, A., Sanseau, P., Cavalla, D., & Pirmohamed, M. (2019). Drug repurposing: Progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1), 41-58. https://doi.org/10.1038/nrd.2018.168
59. Scannell, J. W., Blanckley, A., Boldon, H., & Warrington, B. (2012). Diagnosing the decline in pharmaceutical R&D efficiency. Nature Reviews Drug Discovery, 11, 191-200. https://doi.org/10.1038/nrd3681
60. Schrijvers, R. (2013). Etravirine for the treatment of HIV/AIDS. Expert Opinion on Pharmacotherapy, 14(8), 1087-1096. https://doi.org/10.1517/14656566.2013.787411
61. Shiraki, K. (2018). Antiviral drugs against alphaherpesvirus. Advances in Experimental Medicine and Biology, 1045, 103-122. https://doi.org/10.1007/978-981-10-7230-7_6
62. Singh, T., Biswas, D., & Jayaram, B. (2011). AADS-An automated active site identification, docking, and scoring protocol for protein targets based on physicochemical descriptors. Journal of Chemical Information and Modeling, 51(10), 2515-2527. https://doi.org/10.1021/ci200193z
63. Snoeck, R. (2000). Antiviral therapy of herpes simplex. International Journal of Antimicrobial Agents, 16(2), 157-159. https://doi.org/10.1016/S0924-8579(00)00233-8
64. Tarbouriech, N., Ducournau, C., Hutin, S., Mas, P. J., Man, P., Forest, E., Hart, D. J., Peyrefitte, C. N., Burmeister, W. P., & Iseni, F. (2017). The vaccinia virus DNA polymerase structure provides insights into the mode of processivity factor binding. Nature Communications, 8(1), Article 1455. https://doi.org/10.1038/s41467-017-01542-z
65. Turkez, H., Arslan, M. E., Selvitopi, H., Kadi, A., Oner, S., & Mardinoglu, A. (2023). Drug synergism of anticancer action in combination with favipiravir and paclitaxel on neuroblastoma cells. Medicina, 60(1), Article 82. https://doi.org/10.3390/medicina60010082
66. Ye, F., Song, J., Zhao, L., Zhang, Y., Xia, L., Zhu, L., Kamara, I. L., Ren, J., Wang, W., Tian, H., Wu, G., & Tan, W. (2019). Molecular evidence of human monkeypox virus infection, Sierra Leone. Emerging Infectious Diseases, 25(6), 1220-1222. https://doi.org/https://doi.org/10.3201/eid2506.180296
67. Yuan, S., Chan, H. S., & Hu, Z. (2017). Using PyMOL as a platform for computational drug design. Wiley Interdisciplinary Reviews: Computational Molecular Science, 7(2), Article e1298. https://doi.org/10.1002/wcms.1298
68. Yu, J., & Raj, S. M. (2019). Efficacy of three key antiviral drugs used to treat orthopoxvirus infections: A systematic review. Global Biosecurity, 1(1), Article 28. https://doi.org/10.31646/gbio.12
69. Wei, T., Najmi, S. M., Liu, H., Peltonen, K., Kucerova, A., Schneider, D. A., & Laiho, M. (2018). Small-molecule targeting of RNA polymerase I activates a conserved transcription elongation checkpoint. Cell Reports, 23(2), 404-414. https://doi.org/10.1016/j.celrep.2018.03.066
70. Wu, J., Hu, B., Lu, S., Duan, R., Deng, H., Li, L., He, L., Zhao, Y., Wang, J., & Yu, Z. (2022). Identification of raloxifene as a novel α-glucosidase inhibitor using a systematic drug repurposing approach in combination with cross molecular docking-based virtual screening and experimental verification. Carbohydrate Research, 511, Article 108478. https://doi.org/10.1016/j.carres.2021.108478
71. Wu, Z., Drach, J. C., Prichard, M. N., Yanachkova, M., Yanachkov, I., Bowlin, T. L., & Zemlicka, J. (2009). L-valine ester of cyclopropavir: A new antiviral prodrug. Antiviral Chemistry and Chemotherapy, 20(1), 37-46. https://doi.org/10.3851/IMP782
72. Zhou, Y. D., Kim, Y. P., Mohammed, K. A., Jones, D. K., Muhammad, I., Dunbar, D. C., & Nagle, D. G. (2005). Terpenoid tetrahydroisoquinoline alkaloids emetine, klugine, and isocephaeline inhibit the activation of hypoxia-inducible factor-1 in breast tumor cells. Journal of Natural Products, 68(6), 947-950. https://doi.org/10.1021/np050029m
73. Zumla, A., Valdoleiros, S. R., Haider, N., Asogun, D., Ntoumi, F., Petersen, E., & Kock, R. (2022). Monkeypox outbreaks outside endemic regions: Scientific and social priorities. The Lancet Infectious Diseases, 22(7), 929-931. https://doi.org/10.1016/S1473-3099(22)00354-1