Current Science

Open Access Open Access  Restricted Access Subscription Access

Antiviral drugs prioritization for COVID-19 management based on rational selection


Affiliations
1 Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
2 Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
3 INTOX Private Limited, Pune 412 115, India
 

The SARS-CoV-2 infection has resulted in COVID-19 pandemic worldwide. It has infected around 0.1 billion individuals and caused 2 million fatalities across the globe till mid-January 2021. Drug repurposing has been utilized as the most preferred therapeutic intervention for COVID-19 mitigation due to its necessity and feasibility. To prioritize therapeutic regime against COVID-19, we used 61 antiviral drugs and their combinations. Selected molecules were subjected to virtual screening against: (i) human angiotensin-converting enzyme 2 receptor binding domain (hACE-2) which serves as an anchor for virus attachment and entry, (ii) SARS-CoV-2 RNA dependent RNA polymerase (RdRp) responsible for viral RNA replication, and (iii) SARS-CoV-2 main protease (MPro) needed for viral polyprotein slab proteolytic processing. Based on docking score, pharmacodynamic and pharmacokinetic parameters, combinations of Daclatasvir, Elbasvir, Indinavir, Ledipasvir, Paritaprevir and Rilpivirine were analysed further. Our analysis suggested Sofosbuvir in combination with Ledipasvir and Daclatasvir as potential therapeutic agents for SARS-CoV-2. The combined score suggests that these combinations have superior antiSARS-CoV-2 potential than Remdesivir and other investigational drugs. The present work provides a rationale-based approach to select drugs with possible anti-SARS-CoV-2 activity for further clinical evaluation.

Keywords

Drug repurposing, hACE-2, main protease, RNA dependent RNA polymerase, SARS-CoV-2
User
Notifications
Font Size

  • WHO, Coronavirus disease. World Health Organization, 2020, 2633.

  • Thorlund, K., Dron, L., Park, J., Hsu, G., Forrest, J. I. and Mills, E. J., A real-time dashboard of clinical trials for COVID-19. Lancet Digit. Health, 2020, 7500, 2019–2020.

  • Shaffer, L., 15 drugs being tested to treat COVID-19 and how they would work. Nat. Med., 2020.

  • Joshi, R. S. et al., Discovery of potential multi-target-directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease. J. Biomol. Struct. Dyn., 2020, 5, 1–16.

  • Hoffmann, M. et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 2020, 181, 1–10.

  • Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T. and Veesler, D., Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 2020, 181, 281–292.e6.

  • Shang, J. et al., Structural basis of receptor recognition by SARSCoV-2. Nature, 2020, 581, 1–8.

  • Li, F., Structure, function, and evolution of coronavirus spike proteins. Annu. Rev. Virol., 2016, 3, 237–261.

  • Gao, Y. et al., Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, 2020, 7498, 1–9.

  • Amirian, E. S. and Levy, J. K., Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health, 2020, 9, 100128.

  • Zhang, L. et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved -ketoamide inhibitors. Science, 2020, 3405, 1–9.

  • Krichel, B., Falke, S., Hilgenfeld, R. and Redecke, L., Processing of the SARS-CoV pp1a/ab nsp7–10 region. Biochem. J., 2020, 477, 1009–1019.

  • Anand, K., Ziebuhr, J., Wadhwani, P., Mesters, J. R. and Hilgenfeld, R., Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science, 2003, 300, 1763– 1767.

  • Kim, S. et al., PubChem 2019 update: improved access to chemical data. Nucleic Acids Res., 2018, 47, D1102–D1109.

  • Morris, G. and Huey, R., AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30, 2785–2791.

  • Trott, O. and Olson, A. J., AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31, 455–461.

  • Cao, B. et al., A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N. Engl. J. Med., 2020, 1–13.

  • Muralidharan, N., Sakthivel, R., Velmurugan, D. and Gromiha, M. M., Computational studies of drug repurposing and synergism of lopinavir, oseltamivir and ritonavir binding with SARS-CoV-2 protease against COVID-19. J. Biomol. Struct. Dyn., 2020, 1–7 (at press).

  • Chen, C. et al., Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv, 2020, 2020.03.17.20037432.

  • Kumari, R. and Nguyen, M. H., Fixed-dose combination of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C genotype 1. Exp. Opin. Pharmacother., 2015, 16, 739–748.

  • Belema, M. et al., Hepatitis C virus NS5A replication complex inhibitors: the discovery of daclatasvir. J. Med. Chem., 2014, 57, 2013–2032.

  • Chung, R., AASLD/IDSA HCV guidance: recommendations for testing, managing, and treating hepatitis C. Clin. Liver Dis., 2018, 12, 117.

  • Younossi, Z. M. et al., Patient-reported outcomes in chronic hepatitis C patients with cirrhosis treated with Sofobuvircontaining regimens. Hepatology, 2015, 61, 1798–1808.

  • Xia, Q., Radzio, J., Anderson, K. S. and Sluis-Cremer, N., Probing non-nucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses. Protein Sci., 2007, 16, 1728–1737.

  • Fernández-Montero, J. V., Vispo, E., Anta, L., de Mendoza, C. and Soriano, V., Rilpivirine: a next-generation non-nucleoside analogue for the treatment of HIV infection. Exp. Opin. Pharmacother., 2012, 13, 1007–1014.

  • Fantauzzi, A. and Mezzaroma, I., Dolutegravir: clinical efficacy and role in HIV therapy. Ther. Adv. Chronic Dis., 2014, 5, 164– 177.

  • Zamora, F. and Ogbuagu, O., Dolutegravir/rilpivirine for the treatment of HIV-1 infection. HIV AIDS (Auckl), 2018, 10, 215– 224.

  • Klibanov, O. M., Gale, S. E. and Santevecchi, B., Ombitasvir/ paritaprevir/ritonavir and dasabuvir tablets for hepatitis C virus genotype 1 infection. Ann. Pharmacother., 2015, 49, 566–581.

  • Hull, M. W. and Montaner, J. S. G., Ritonavir-boosted protease inhibitors in HIV therapy. Ann. Med., 2011, 43, 375–388.

  • Faletto, M. B., Miller, W. H., Garvey, E. P., St. Clair, M. H., Daluge, S. M. and Good, S. S., Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob. Agents Chemother., 1997, 41, 1099–1107.

  • Bell, A. M., Wagner, J. L., Barber, K. E. and Stover, K. R., Elbasvir/grazoprevir: a review of the latest agent in the fight against hepatitis C. Int. J. Hepatol., 2016, 2016.

  • Vishal, M., Pravin, D., Himani, G., Nilam, V., Urvisha, B. and Rajesh, P., Drug repurposing of approved drugs elbasvir, ledipasvir, paritaprevir, velpatasvir, antrafenine and ergotamine for combating COVID-19. chemRxiv, 2020.

  • Omotuyi, O. et al., The disruption of SARS-CoV-2 RBD/ACE-2 complex by ubrogepant is mediated by interface hydration. Preprints, 2020, 2020030466.

  • Cure, E. and Cumhur Cure, M., Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may be harmful in patients with diabetes during COVID-19 pandemic. Diabetes Metab. Syndr., 2020, 14, 349–350.

  • Hasan, A. et al., A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin. J. Biomol. Struct. Dyn., 2020, 1–13 (at press).

  • Yamamoto, M. et al., The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects. Viruses, 2020, 12, 629; doi:10.3390/v12060629.


Abstract Views: 349

PDF Views: 130




  • Antiviral drugs prioritization for COVID-19 management based on rational selection

Abstract Views: 349  |  PDF Views: 130

Authors

Rakesh S. Joshi
Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
Ashok P. Giri
Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
Mahesh J. Kulkarni
Biochemical Sciences Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
Mahesh Gupta
Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
Savita Verma
Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
Dhruva Chaudhry
Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak 124 001, India
Narendra Deshmukh
INTOX Private Limited, Pune 412 115, India
Anita Chugh
INTOX Private Limited, Pune 412 115, India

Abstract


The SARS-CoV-2 infection has resulted in COVID-19 pandemic worldwide. It has infected around 0.1 billion individuals and caused 2 million fatalities across the globe till mid-January 2021. Drug repurposing has been utilized as the most preferred therapeutic intervention for COVID-19 mitigation due to its necessity and feasibility. To prioritize therapeutic regime against COVID-19, we used 61 antiviral drugs and their combinations. Selected molecules were subjected to virtual screening against: (i) human angiotensin-converting enzyme 2 receptor binding domain (hACE-2) which serves as an anchor for virus attachment and entry, (ii) SARS-CoV-2 RNA dependent RNA polymerase (RdRp) responsible for viral RNA replication, and (iii) SARS-CoV-2 main protease (MPro) needed for viral polyprotein slab proteolytic processing. Based on docking score, pharmacodynamic and pharmacokinetic parameters, combinations of Daclatasvir, Elbasvir, Indinavir, Ledipasvir, Paritaprevir and Rilpivirine were analysed further. Our analysis suggested Sofosbuvir in combination with Ledipasvir and Daclatasvir as potential therapeutic agents for SARS-CoV-2. The combined score suggests that these combinations have superior antiSARS-CoV-2 potential than Remdesivir and other investigational drugs. The present work provides a rationale-based approach to select drugs with possible anti-SARS-CoV-2 activity for further clinical evaluation.

Keywords


Drug repurposing, hACE-2, main protease, RNA dependent RNA polymerase, SARS-CoV-2

References





DOI: https://doi.org/10.18520/cs%2Fv120%2Fi9%2F1464-1470