IN SILICO MONKEYPOX RESEARCH: PAVING THE WAY FOR NEXT-GENERATION TREATMENTS AND THERAPIES
Main Article Content
Keywords
Monkeypox Virus, VP39 2'-O Methyltransferase, Physalin A, Sitoindoside IX, Withanolide
Abstract
The global re-emergence of the Monkeypox Virus (MPXV) has sparked renewed efforts to identify effective antiviral treatments. In this study, we conducted an in silico docking analysis using CB Dock2 to evaluate natural products and repurposed antiviral drugs. We focused on key viral targets for inhibition, including VP39 2'-O Methyltransferase, viral topoisomerase-DNA complexes, and poxin. Our findings highlighted several natural compounds, such as Physalin A, Sitoindoside IX, Withanolide, Shatavarin 1, Kutkoside, and Berberine HCl, as potential inhibitors. Additionally, Tecovirimat emerged as the most effective repurposed antiviral. Among the natural products, Withanolide, Sitoindoside IX, and Physalin A demonstrated promising inhibitory potential based on their Vina scores and binding affinities, offering hope for alternative therapeutic options. Tecovirimat remained the most potent inhibitor across all tested targets, underscoring its continued relevance in the fight against MPXV.
References
1. Nuzzo, J. B., Borio, L. L., & Gostin, L. O. (2022). The WHO declaration of monkeypox as a global public health emergency. Jama, 328(7), 615-617.
2. McCollum, A. M., & Damon, I. K. (2014). Human monkeypox. Clinical infectious diseases, 58(2), 260-267
3. Alzhanova, D., Edwards, D. M., Hammarlund, E., Scholz, I. G., Horst, D., Wagner, M. J., ... & Früh, K. (2009). Cowpox virus inhibits the transporter associated with antigen processing to evade T cell recognition. Cell host & microbe, 6(5), 433-445.
4. Hakim, M. S., & Widyaningsih, S. A. (2023). The recent re-emergence of human monkeypox: Would it become endemic beyond Africa. Journal of Infection and Public Health, 16(3), 332-340.
5. Reynolds, M. G., Carroll, D. S., & Karem, K. L. (2012). Factors affecting the likelihood of monkeypox's emergence and spread in the post-smallpox era. Current Opinion in Virology, 2(3), 335-343.
6. Moss, B. (2013). Poxvirus DNA replication. Cold Spring Harbor perspectives in biology, 5(9), a010199
7. Shuman, S. (1991). Recombination mediated by vaccinia virus DNA topoisomerase I in Escherichia coli is sequence specific. Proceedings of the National Academy of Sciences, 88(22), 10104-10108.
8. De Vivo, M., & Cavalli, A. (2017). Recent advances in dynamic docking for drug discovery. Wiley Interdisciplinary Reviews: Computational Molecular Science, 7(6), e1320.
9. Abbas Y, Sajid M, Hussain M, Batool S, Rehman SU, Ahmad J. Clinical features, transmission dynamics, pathogenesis, and diagnostic approaches of monkeypox virus. Hosts and Viruses. 2024;11:101-8.
10. Zgarbova, Michala & Otava, Tomas & Silhan, Jan & Nencka, Radim & Weber, Jan & Boura, Evzen. (2023). Inhibitors of mpox VP39 2′-O methyltransferase efficiently inhibit the monkeypox virus. Antiviral Research. 218. 105714. 10.1016/j.antiviral.2023.105714.
11. Yuta Tsukamoto, Manabu Igarashi, Hiroki Kato, Targeting cap1 RNA methyltransferases as an antiviral strategy, Cell Chemical Biology, Volume 31, Issue 1,2024, Pages 86-99, https://doi.org/10.1016/j.chembiol.2023.11.011.
12. Perry K, Hwang Y, Bushman FD, Van Duyne GD. Insights from the structure of a smallpox virus topoisomerase-DNA transition state mimic. Structure. 2010 Jan 13;18(1):127-37. doi: 10.1016/j.str.2009.10.020. PMID: 20152159; PMCID: PMC2822398.
13. Sagdat K, Batyrkhan A, Kanayeva D. Exploring monkeypox virus proteins and rapid detection techniques. Front Cell Infect Microbiol. 2024 May 28;14:1414224. doi: 10.3389/fcimb.2024.1414224. PMID: 38863833; PMCID: PMC11165096.
14. Hu X, An S, Chu J, Liang B, Liao Y, Jiang J, Lin Y, Ye L, Liang H. Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I. Molecules. 2023 Feb 2;28(3):1444. doi: 10.3390/molecules28031444. PMID: 36771105; PMCID: PMC9919579.
15. Chathuranga K, Weerawardhana A, Dodantenna N, Lee JS. Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing. Exp Mol Med. 2021 Nov;53(11):1647-1668. doi: 10.1038/s12276-021-00691-y. Epub 2021 Nov 16. PMID: 34782737; PMCID: PMC8592830.
16. Duchoslav V, Boura E. Structure of monkeypox virus poxin: implications for drug design. Arch Virol. 2023 Jun 28;168(7):192. doi: 10.1007/s00705-023-05824-4. PMID: 37378908; PMCID: PMC10307694.
17. Xue-Mei Yi, Ya-Li Lei, Mi Li, Li Zhong, Shu Li, The monkeypox virus-host interplays, Cell Insight,Volume 3, Issue 5, 2024, 100185, ISSN 2772-8927, https://doi.org/10.1016/j.cellin.2024.100185.
18. Bruno Hernáez et al. Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection.Sci. Adv.6 ,eabb4565(2020).DOI:10.1126/sciadv.abb4565
19. Bachar, S. C., Mazumder, K., Bachar, R., Aktar, A., & Al Mahtab, M. (2021). A review of medicinal plants with antiviral activity available in Bangladesh and mechanistic insight into their bioactive metabolites on SARS-CoV-2, HIV and HBV. Frontiers in Pharmacology, 12, 732891.
20. Byrareddy SN, Sharma K, Sachdev S, Reddy AS, Acharya A, Klaustermeier KM, Lorson CL, Singh K. Potential therapeutic targets for Mpox: the evidence to date. Expert Opin Ther Targets. 2023 Jan-Jun;27(6):419-431. doi: 10.1080/14728222.2023.2230361. Epub 2023 Jul 4. PMID: 37368464; PMCID: PMC10722886.
21. O'Laughlin K, Tobolowsky FA, Elmor R, Overton R, O'Connor SM, Damon IK, Petersen BW, Rao AK, Chatham-Stephens K, Yu P, Yu Y; CDC Monkeypox Tecovirimat Data Abstraction Team. Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol - United States, May-August 2022. MMWR Morb Mortal Wkly Rep. 2022 Sep 16;71(37):1190-1195. doi: 10.15585/mmwr.mm7137e1. PMID: 36107794; PMCID: PMC9484807.
22. Abbas Y, Sajid M, Hussain M, Batool S, Rehman SU, Ahmad J. Clinical features, transmission dynamics, pathogenesis, and diagnostic approaches of monkeypox virus. Hosts and Viruses. 2024;11:101-8.
23. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Brincidofovir. [Updated 2022 Oct 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585270/
24. DeLaurentis CE, Kiser J, Zucker J. New Perspectives on Antimicrobial Agents: Tecovirimat for Treatment of Human Monkeypox Virus. Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0122622. doi: 10.1128/aac.01226-22. Epub 2022 Nov 14. PMID: 36374026; PMCID: PMC9765296.
25. Ribeiro-Filho J, Teles YCF, Igoli JO, Capasso R. Editorial: New trends in natural product research for inflammatory and infectious diseases. Front Pharmacol. 2022 Aug 15;13:975079. doi: 10.3389/fphar.2022.975079. PMID: 36046835; PMCID: PMC9421362.
26. Akram, Muhammad & Mandal, Anirban & Mukherjee, Arindam & Bandyopadhyay, Ritika & Rangasamy, Surendar & Zainab, Rida & Khalil, Muhammad & Parmar, Pragnesh & Laila, Umme. (2024). Inhibitory Potential of Medicinal Plants Against Viral Pathogens and their Putative Modes of Action. Hosts and Viruses. 10. 10.17582/journal.hv/2023/10.58.71.
27. Ozeer, F.Z., Nagandran, S., Wu, Y.S. et al. A comprehensive review of phytochemicals of Withania somnifera (L.) Dunal (Solanaceae) as antiviral therapeutics. Discov Appl Sci 6, 187 (2024). https://doi.org/10.1007/s42452-024-05845-x
28. Jayaprakasam, B., Zhang, Y., Seeram, N. P., & Nair, M. G. (2003). Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves. Life sciences, 74(1), 125-132.
29. Chikhale RV, Sinha SK, Patil RB, Prasad SK, Shakya A, Gurav N, Prasad R, Dhaswadikar SR, Wanjari M, Gurav SS. In-silico investigation of phytochemicals from Asparagus racemosus as plausible antiviral agent in COVID-19. J Biomol Struct Dyn. 2021 Sep;39(14):5033-5047. doi: 10.1080/07391102.2020.1784289. Epub 2020 Jun 24. PMID: 32579064; PMCID: PMC7335809.
30. Bhattacharjee, Siddhendu & Bhattacharya, Sibasis & Jana, Sampriti. (2013). A REVIEW ON MEDICINALLY IMPORTANT SPECIES OF PICRORHIZA A REVIEW ON MEDICINALLY IMPORTANT SPECIES OF PICRORHIZA. 2. 1-16.
31. Warowicka A, Nawrot R, Gozdzicka-Jozefiak A. Antiviral activity of berberine. Arch Virol. 2020 Sep;165(9):1935-1945. doi: 10.1007/s00705-020-04706-3. Epub 2020 Jun 28. PMID: 32594322; PMCID: PMC7320912.
32. Eurosurveillance editorial team. Note from the editors: WHO declares mpox outbreak a public health emergency of international concern. Euro Surveill. 2024;29(33): pii=240815v. https://doi.org/10.2807/1560-7917.ES.2024.29.33.240815v
33. Masirika Leandre Murhula, Udahemuka Jean Claude, Schuele Leonard, Ndishimye Pacifique, Otani Saria, Mbiribindi Justin Bengehya, Marekani Jean M., Mambo Léandre Mutimbwa, Bubala Nadine Malyamungu, Boter Marjan, Nieuwenhuijse David F., Lang Trudie, Kalalizi Ernest Balyahamwabo, Musabyimana Jean Pierre, Aarestrup Frank M., Koopmans Marion, Oude Munnink Bas B., Siangoli Freddy Belesi. Ongoing mpox outbreak in Kamituga, South Kivu province, associated with monkeypox virus of a novel Clade I sub-lineage, Democratic Republic of the Congo, 2024. Euro Surveill. 2024;29(11):pii=2400106. https://doi.org/10.2807/1560-7917.ES.2024.29.11.2400106
34. Yang Liu, Xiaocong Yang, Jianhong Gan, Shuang Chen, Zhi-Xiong Xiao, Yang Cao, CB-Dock2: improved protein–ligand blind docking by integrating cavity detection, docking and homologous template fitting, Nucleic Acids Research, Volume 50, Issue W1, 5 July 2022, Pages W159–W164, https://doi.org/10.1093/nar/gkac394
35. Abbas Y, Sajid M, Hussain M, Batool S, Rehman SU, Ahmad J. Clinical features, transmission dynamics, pathogenesis, and diagnostic approaches of monkeypox virus. Hosts and Viruses. 2024;11:101-8.
2. McCollum, A. M., & Damon, I. K. (2014). Human monkeypox. Clinical infectious diseases, 58(2), 260-267
3. Alzhanova, D., Edwards, D. M., Hammarlund, E., Scholz, I. G., Horst, D., Wagner, M. J., ... & Früh, K. (2009). Cowpox virus inhibits the transporter associated with antigen processing to evade T cell recognition. Cell host & microbe, 6(5), 433-445.
4. Hakim, M. S., & Widyaningsih, S. A. (2023). The recent re-emergence of human monkeypox: Would it become endemic beyond Africa. Journal of Infection and Public Health, 16(3), 332-340.
5. Reynolds, M. G., Carroll, D. S., & Karem, K. L. (2012). Factors affecting the likelihood of monkeypox's emergence and spread in the post-smallpox era. Current Opinion in Virology, 2(3), 335-343.
6. Moss, B. (2013). Poxvirus DNA replication. Cold Spring Harbor perspectives in biology, 5(9), a010199
7. Shuman, S. (1991). Recombination mediated by vaccinia virus DNA topoisomerase I in Escherichia coli is sequence specific. Proceedings of the National Academy of Sciences, 88(22), 10104-10108.
8. De Vivo, M., & Cavalli, A. (2017). Recent advances in dynamic docking for drug discovery. Wiley Interdisciplinary Reviews: Computational Molecular Science, 7(6), e1320.
9. Abbas Y, Sajid M, Hussain M, Batool S, Rehman SU, Ahmad J. Clinical features, transmission dynamics, pathogenesis, and diagnostic approaches of monkeypox virus. Hosts and Viruses. 2024;11:101-8.
10. Zgarbova, Michala & Otava, Tomas & Silhan, Jan & Nencka, Radim & Weber, Jan & Boura, Evzen. (2023). Inhibitors of mpox VP39 2′-O methyltransferase efficiently inhibit the monkeypox virus. Antiviral Research. 218. 105714. 10.1016/j.antiviral.2023.105714.
11. Yuta Tsukamoto, Manabu Igarashi, Hiroki Kato, Targeting cap1 RNA methyltransferases as an antiviral strategy, Cell Chemical Biology, Volume 31, Issue 1,2024, Pages 86-99, https://doi.org/10.1016/j.chembiol.2023.11.011.
12. Perry K, Hwang Y, Bushman FD, Van Duyne GD. Insights from the structure of a smallpox virus topoisomerase-DNA transition state mimic. Structure. 2010 Jan 13;18(1):127-37. doi: 10.1016/j.str.2009.10.020. PMID: 20152159; PMCID: PMC2822398.
13. Sagdat K, Batyrkhan A, Kanayeva D. Exploring monkeypox virus proteins and rapid detection techniques. Front Cell Infect Microbiol. 2024 May 28;14:1414224. doi: 10.3389/fcimb.2024.1414224. PMID: 38863833; PMCID: PMC11165096.
14. Hu X, An S, Chu J, Liang B, Liao Y, Jiang J, Lin Y, Ye L, Liang H. Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I. Molecules. 2023 Feb 2;28(3):1444. doi: 10.3390/molecules28031444. PMID: 36771105; PMCID: PMC9919579.
15. Chathuranga K, Weerawardhana A, Dodantenna N, Lee JS. Regulation of antiviral innate immune signaling and viral evasion following viral genome sensing. Exp Mol Med. 2021 Nov;53(11):1647-1668. doi: 10.1038/s12276-021-00691-y. Epub 2021 Nov 16. PMID: 34782737; PMCID: PMC8592830.
16. Duchoslav V, Boura E. Structure of monkeypox virus poxin: implications for drug design. Arch Virol. 2023 Jun 28;168(7):192. doi: 10.1007/s00705-023-05824-4. PMID: 37378908; PMCID: PMC10307694.
17. Xue-Mei Yi, Ya-Li Lei, Mi Li, Li Zhong, Shu Li, The monkeypox virus-host interplays, Cell Insight,Volume 3, Issue 5, 2024, 100185, ISSN 2772-8927, https://doi.org/10.1016/j.cellin.2024.100185.
18. Bruno Hernáez et al. Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection.Sci. Adv.6 ,eabb4565(2020).DOI:10.1126/sciadv.abb4565
19. Bachar, S. C., Mazumder, K., Bachar, R., Aktar, A., & Al Mahtab, M. (2021). A review of medicinal plants with antiviral activity available in Bangladesh and mechanistic insight into their bioactive metabolites on SARS-CoV-2, HIV and HBV. Frontiers in Pharmacology, 12, 732891.
20. Byrareddy SN, Sharma K, Sachdev S, Reddy AS, Acharya A, Klaustermeier KM, Lorson CL, Singh K. Potential therapeutic targets for Mpox: the evidence to date. Expert Opin Ther Targets. 2023 Jan-Jun;27(6):419-431. doi: 10.1080/14728222.2023.2230361. Epub 2023 Jul 4. PMID: 37368464; PMCID: PMC10722886.
21. O'Laughlin K, Tobolowsky FA, Elmor R, Overton R, O'Connor SM, Damon IK, Petersen BW, Rao AK, Chatham-Stephens K, Yu P, Yu Y; CDC Monkeypox Tecovirimat Data Abstraction Team. Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol - United States, May-August 2022. MMWR Morb Mortal Wkly Rep. 2022 Sep 16;71(37):1190-1195. doi: 10.15585/mmwr.mm7137e1. PMID: 36107794; PMCID: PMC9484807.
22. Abbas Y, Sajid M, Hussain M, Batool S, Rehman SU, Ahmad J. Clinical features, transmission dynamics, pathogenesis, and diagnostic approaches of monkeypox virus. Hosts and Viruses. 2024;11:101-8.
23. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Brincidofovir. [Updated 2022 Oct 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585270/
24. DeLaurentis CE, Kiser J, Zucker J. New Perspectives on Antimicrobial Agents: Tecovirimat for Treatment of Human Monkeypox Virus. Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0122622. doi: 10.1128/aac.01226-22. Epub 2022 Nov 14. PMID: 36374026; PMCID: PMC9765296.
25. Ribeiro-Filho J, Teles YCF, Igoli JO, Capasso R. Editorial: New trends in natural product research for inflammatory and infectious diseases. Front Pharmacol. 2022 Aug 15;13:975079. doi: 10.3389/fphar.2022.975079. PMID: 36046835; PMCID: PMC9421362.
26. Akram, Muhammad & Mandal, Anirban & Mukherjee, Arindam & Bandyopadhyay, Ritika & Rangasamy, Surendar & Zainab, Rida & Khalil, Muhammad & Parmar, Pragnesh & Laila, Umme. (2024). Inhibitory Potential of Medicinal Plants Against Viral Pathogens and their Putative Modes of Action. Hosts and Viruses. 10. 10.17582/journal.hv/2023/10.58.71.
27. Ozeer, F.Z., Nagandran, S., Wu, Y.S. et al. A comprehensive review of phytochemicals of Withania somnifera (L.) Dunal (Solanaceae) as antiviral therapeutics. Discov Appl Sci 6, 187 (2024). https://doi.org/10.1007/s42452-024-05845-x
28. Jayaprakasam, B., Zhang, Y., Seeram, N. P., & Nair, M. G. (2003). Growth inhibition of human tumor cell lines by withanolides from Withania somnifera leaves. Life sciences, 74(1), 125-132.
29. Chikhale RV, Sinha SK, Patil RB, Prasad SK, Shakya A, Gurav N, Prasad R, Dhaswadikar SR, Wanjari M, Gurav SS. In-silico investigation of phytochemicals from Asparagus racemosus as plausible antiviral agent in COVID-19. J Biomol Struct Dyn. 2021 Sep;39(14):5033-5047. doi: 10.1080/07391102.2020.1784289. Epub 2020 Jun 24. PMID: 32579064; PMCID: PMC7335809.
30. Bhattacharjee, Siddhendu & Bhattacharya, Sibasis & Jana, Sampriti. (2013). A REVIEW ON MEDICINALLY IMPORTANT SPECIES OF PICRORHIZA A REVIEW ON MEDICINALLY IMPORTANT SPECIES OF PICRORHIZA. 2. 1-16.
31. Warowicka A, Nawrot R, Gozdzicka-Jozefiak A. Antiviral activity of berberine. Arch Virol. 2020 Sep;165(9):1935-1945. doi: 10.1007/s00705-020-04706-3. Epub 2020 Jun 28. PMID: 32594322; PMCID: PMC7320912.
32. Eurosurveillance editorial team. Note from the editors: WHO declares mpox outbreak a public health emergency of international concern. Euro Surveill. 2024;29(33): pii=240815v. https://doi.org/10.2807/1560-7917.ES.2024.29.33.240815v
33. Masirika Leandre Murhula, Udahemuka Jean Claude, Schuele Leonard, Ndishimye Pacifique, Otani Saria, Mbiribindi Justin Bengehya, Marekani Jean M., Mambo Léandre Mutimbwa, Bubala Nadine Malyamungu, Boter Marjan, Nieuwenhuijse David F., Lang Trudie, Kalalizi Ernest Balyahamwabo, Musabyimana Jean Pierre, Aarestrup Frank M., Koopmans Marion, Oude Munnink Bas B., Siangoli Freddy Belesi. Ongoing mpox outbreak in Kamituga, South Kivu province, associated with monkeypox virus of a novel Clade I sub-lineage, Democratic Republic of the Congo, 2024. Euro Surveill. 2024;29(11):pii=2400106. https://doi.org/10.2807/1560-7917.ES.2024.29.11.2400106
34. Yang Liu, Xiaocong Yang, Jianhong Gan, Shuang Chen, Zhi-Xiong Xiao, Yang Cao, CB-Dock2: improved protein–ligand blind docking by integrating cavity detection, docking and homologous template fitting, Nucleic Acids Research, Volume 50, Issue W1, 5 July 2022, Pages W159–W164, https://doi.org/10.1093/nar/gkac394
35. Abbas Y, Sajid M, Hussain M, Batool S, Rehman SU, Ahmad J. Clinical features, transmission dynamics, pathogenesis, and diagnostic approaches of monkeypox virus. Hosts and Viruses. 2024;11:101-8.
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Feb 11, 2025
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Muhammad Sajid, Zeeshan Hussain Shah, Uswa Sajid, Qandeel Abbas Soomro, Muhammad Taqi, Maheen Zahra, Syeda Qurbat Zahra, Munir Hussain, & Zaighum Abbas. (2025). IN SILICO MONKEYPOX RESEARCH: PAVING THE WAY FOR NEXT-GENERATION TREATMENTS AND THERAPIES. Journal of Population Therapeutics and Clinical Pharmacology, 32(1), 774-784. https://doi.org/10.53555/519stv80
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Author Biographies
Muhammad Sajid
Faculty of Veterinary Sciences, University of Agriculture Faisalabad Pakistan.
Zeeshan Hussain Shah
Department of Biological Sciences, Gomal University, Pakistan.
Uswa Sajid
Department of Zoology Hazara University Mansehra, Pakistan.
Qandeel Abbas Soomro
Deparment of Pathology, Indus Medical College Tando Muhammad Khan, Pakistan.
Muhammad Taqi
Department of Pharmacy, Shah Abdul Latif University, Pakistan.
Maheen Zahra
Gomal Centre of Biochemistry and Biotechnology, Gomal University Dera Ismail Khan, Pakistan.
Syeda Qurbat Zahra
Gomal Centre of Biochemistry and Biotechnology, Gomal University Dera Ismail Khan, Pakistan.
Munir Hussain
Faculty of Animal Husbandry and Veterinary Science, Sindh Agriculture University Tandojam, Pakistan
Zaighum Abbas
Department of Biotechnology, University of Sialkot Pakistan.
How to Cite
Muhammad Sajid, Zeeshan Hussain Shah, Uswa Sajid, Qandeel Abbas Soomro, Muhammad Taqi, Maheen Zahra, Syeda Qurbat Zahra, Munir Hussain, & Zaighum Abbas. (2025). IN SILICO MONKEYPOX RESEARCH: PAVING THE WAY FOR NEXT-GENERATION TREATMENTS AND THERAPIES. Journal of Population Therapeutics and Clinical Pharmacology, 32(1), 774-784. https://doi.org/10.53555/519stv80