The role of SARS-COV-2 -Main Protease: the case of Gepants family and Veruprevir

Ivan Vito Ferrari¹ , Paolo Patrizio² , Mauro Di Mario³ , Blasco Morozzo Della Rocca⁴

Section:Research Paper, Product Type: Journal-Paper
Vol.10 , Issue.3 , pp.34-40, Jun-2023

Online published on Jun 30, 2023

Copyright © Ivan Vito Ferrari, Paolo Patrizio, Mauro Di Mario, Blasco Morozzo Della Rocca . This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
 

View this paper at   Google Scholar | DPI Digital Library

XML View     PDF Download

How to Cite this Paper

Abstract :
In this study, our approach was to conduct a complete investigation of molecular docking analysis with the major SARS-CoV-2 proteins and SARS CoV-1 proteins. We analyzed more than 6000 drugs, downloaded by the Pubchem database. Particular attention, we have focused on 3CLpro Covid-19 protein, by “Blind docking” method and “Selective docking” procedure, in Ligand Binding site, with Autodock Vina using Pyrx, a small Virtual Screen Library, and with Autodock 4 using AMDock Software. We have selected about 30 drugs with a high-affinity Binding score (between- 9.7 and-12 kcal/mol) from our results. Next, carrying out docking Validation methods, using Human Serum Albumin, as a docking control protein, has led us to select only the three best drugs (Ubrogepant, Atogepant, and Paritaprevir), potentially active in the Ligand Binding site pocket of 3CL-pro SARS-CoV-2 protein. Ubrogepant and Atogepant, have Ki values around, 20 -25 nM and Binding Energy of approximately -10 kcal/mol, except for Paritaprevir which reports exceptional Ki values of approximately 1nM and Binding Energy of approximately - 12.5 kcal/mol. This has led us to conclude, that they could be excellent candidates against SARS-COV-2, even though further in vitro and in vivo studies are needed.

Key-Words / Index Term :
SARS-CoV-2, Docking analysis and Gepants

References :
[1] Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G. F.; Tan, W. A “Novel Coronavirus from Patients with Pneumonia in China”, 2019. New England Journal of Medicine , pp. 727–733,2020.
[2] Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; Xia, J.; Yu, T.; Zhang, X.; Zhang, L. Epidemiological and Clinical Characteristics of 99 Cases of 2019 Novel Coronavirus Pneumonia in Wuhan, China: A Descriptive Study. The Lancet , Vol.395 , pp. 507–513,2020
[3] Gautier, J. F.; Ravussin, Y. A New Symptom of COVID-19: Loss of Taste and Smell. Obesity. Blackwell Publishing Inc,Vol85.,pp.848,2020
[4] Nobel, Y. R.; Phipps, M.; Zucker, J.; Lebwohl, B.; Wang, T. C.; Sobieszczyk, M. E.; Freedberg, D. E. Gastrointestinal Symptoms and Coronavirus Disease 2019: A Case-Control Study From the United States. Gastroenterology, Vol.159 ,pp. 373-375,2020
[5] Kluytmans-Van Den Bergh, M. F. Q.; Buiting, A. G. M.; Pas, S. D.; Bentvelsen, R. G.; van den Bijllaardt, W.; van Oudheusden, A. J. G.; van Rijen, M. M. L.; Verweij, J. J.; Koopmans, M. P. G.; Kluytmans, J. A. J. W. Prevalence and Clinical Presentation of Health Care Workers with Symptoms of Coronavirus Disease 2019 in 2 Dutch Hospitals during an Early Phase of the Pandemic. JAMA Network Open 2020.
[6] Lovato, A.; de Filippis, C.; Marioni, G. Upper Airway Symptoms in Coronavirus Disease 2019 (COVID-19). American Journal of Otolaryngology - Head and Neck Medicine and Surgery. W.B. Saunders,2020.
[7] Gupta, G.; Singh, Y.; Chellappan, D.; Dua, K. Emerging Dermatological Symptoms in Coronavirus Pandemic. Journal of Cosmetic Dermatology. Blackwell Publishing Ltd 2447–2448,2020.
[8] Vaira, L. A.; Salzano, G.; Deiana, G.; de Riu, G. Anosmia and Ageusia: Common Findings in COVID-19 Patients. Laryngoscope ,Vol. 130 , pp.1787,2020.
[9] Alejandro Gómez-Ochoa, S.; Franco, O. H.; Rojas, L. Z.;Raguindin, P. F.; Roa-Díaz, M.; Wyssmann, B. M.; Lucrecia, S.; Guevara, R.; Echeverría, L. E.; Glisic, M.; Muka, T. COVID-19 in Healthcare Workers: A Living Systematic Review and Meta-Analysis of Prevalence, Risk Factors, Clinical Characteristics, and Outcomes.
[10] Cao, X. COVID-19: Immunopathology and Its Implications for Therapy. Nature Reviews Immunology. Nature Research, Vol 20,pp.269–270,2020.
[11] Basile, C.; Combe, C.; Pizzarelli, F.; Covic, A.; Davenport, A.; Kanbay, M.; Kirmizis, Di.; Schneditz, D.; van der Sande, F.; Mitra, S. Recommendations for the Prevention, Mitigation and Containment of the Emerging SARS-CoV-2 (COVID-19) Pandemic in Haemodialysis Centres. Nephrology Dialysis Transplantation , Vol.35, pp.737-741,2020.
[12] Sabetkish, N.; Rahmani, A. The Overall Impact of COVID ?19 on Healthcare during the Pandemic: A Multidisciplinary Point of View. Health Science Reports , Vol.4, Issue.(4),p.e386,2021
[13] González, J. M.; Gomez-Puertas, P.; Cavanagh, D.; Gorbalenya, A. E.; Enjuanes, L. A Comparative Sequence Analysis to Revise the Current Taxonomy of the Family Coronaviridae. Archives of Virology ,Vol. 148 (11), 2207–2235Zhu, M. SARS Immunity and Vaccination; Vol. 1(3), 193-198,2003.
[14] Kandeel, M.; Ibrahim, A.; Fayez, M.; Al-Nazawi, M. From SARS and MERS CoVs to SARS-CoV-2: Moving toward More Biased Codon Usage in Viral Structural and Nonstructural Genes. Journal of Medical Virology ,Vol 92,p. 660–666,2020.
[15] Zhu, M. SARS Immunity and Vaccination; Vol1,p.3-198,2004.
[16] Azhar, E. I.; El-Kafrawy, S. A.; Farraj, S. A.; Hassan, A. M.; Al-Saeed, M. S.; Hashem, A. M.; Madani, T. A. Evidence for Camel-to-Human Transmission of MERS Coronavirus. New England Journal of Medicine , Vol.370 ,pp. 2499–2505,2014.
[17] Ita, K. Coronavirus Disease (COVID-19): Current Status and Prospects for Drug and Vaccine Development. Archives of Medical Research. Elsevier Inc.,52, pp.15–24,2021.
[18] Gil, C.; Ginex, T.; Maestro, I.; Nozal, V.; Barrado-Gil, L.; Cuesta-Geijo, . Á.; Urquiza, J.; Ramírez, D.; Alonso, C.; Campillo, N. E.; Martinez, A. COVID-19: Drug Targets and Potential Treatments. Journal of Medicinal Chemistry. American Chemical Society , Vol.63 p.12359–12386, 2020.
[19] Tahir ul Qamar, M.; Alqahtani, S. M.; Alamri, M. A.; Chen, L. L. Structural Basis of SARS-CoV-2 3CLpro and Anti-COVID-19 Drug Discovery from Medicinal Plants. Journal of Pharmaceutical Analysis, Vol.10 ,pp. 313–319,2020.
[20] Mody, V.; Ho, J.; Wills, S.; Mawri, A.; Lawson, L.; Ebert, M. C. C. J. C.; Fortin, G. M.; Rayalam, S.; Taval, S. Identification of 3-Chymotrypsin like Protease (3CLPro) Inhibitors as Potential Anti-SARS-CoV-2 Agents. Communications Biology , Vol.4 , 2021.
(21) Hall, D. C.; Ji, H. F. A Search for Medications to Treat COVID-19 via in Silico Molecular Docking Models of the SARS-CoV-2 Spike Glycoprotein and 3CL Protease. Travel Medicine and Infectious Disease , Vol.35, 101646,2020.
[22] Merck-and-Ridgebacks-Investigational-Oral-Antiviral-Molnupiravir-Reduced-the-Risk-of-Hospitalization-or-Death-by-Approximately-50-Per-C1CSM.
[23] Imran, M.; Kumar Arora, M.; Asdaq, S. M. B.; Khan, S. A.; Alaqel, S. I.; Alshammari, M. K.; Alshehri, M. M.; Alshrari, A. S.; Mateq Ali, A.; Al-Shammeri, A. M.; Alhazmi, B. D.; Harshan, A. A.; Alam, M. T.; Abida. Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for Covid-19. Molecules,Vol.6,pp. 5795,2021.
[24] Painter, W. P.; Holman, W.; Bush, J. A.; Almazedi, F.; Malik, H.; Eraut, N. C. J. E.; Morin, M. J.; Szewczyk, L. J.; Painter, G. R. Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2. Antimicrobial Agents and Chemotherapy 2021,Vol. 65,pp.e02428-20,2021.
[25] Holman, W.; Holman, W.; McIntosh, S.; Painter, W.; Painter, G.; Bush, J.; Cohen, O. Accelerated First-in-Human Clinical Trial of EIDD-2801/MK-4482 (Molnupiravir), a Ribonucleoside Analog with Potent Antiviral Activity against SARS-CoV-2. Trials. BioMed Central Ltd ,Vol.22, pp.1-7,021.
[26] Baum, A.; Fulton, B. O.; Wloga, E.; Copin, R.; Pascal, K. E.; Russo, V.; Giordano, S.; Lanza, K.; Negron, N.; Ni, M.; Wei, Y.; Atwal, G. S.; Murphy, A. J.; Stahl, N.; Yancopoulos, G. D.; Kyratsous, C. A. Antibody Cocktail to SARS-CoV-2 Spike Protein Prevents Rapid Mutational Escape Seen with Individual Antibodies. Science , Vol.369 , pp.1014–1018,2020.
[27] Alanagreh, L.; Alzoughool, F.; Atoum, M. The Human Coronavirus Disease Covid-19: Its Origin, Characteristics, and Insights into Potential Drugs and Its Mechanisms. Pathogens, Vol.9, pp.331,2020.
[28] Dhand, R.; Li, J. Coughs and Sneezes: Their Role in Transmission of Respiratory Viral Infections, Including SARS-CoV-2. American Journal of Respiratory and Critical Care Medicine. American Thoracic Society September 1, Vol.202, pp.651-659 ,2020.
[29] Lazarus, J. v.; Ratzan, S. C.; Palayew, A.; Gostin, L. O.; Larson, H. J.; Rabin, K.; Kimball, S.; El-Mohandes, A. A Global Survey of Potential Acceptance of a COVID-19 Vaccine. Nature Medicine , Vol.27 , pp.225–228,2021.
[30] Thanh Le, T.; Andreadakis, Z.; Kumar, A.; Gómez Román, R.; Tollefsen, S.; Saville, M.; Mayhew, S. The COVID-19 Vaccine Development Landscape. Nature reviews. Drug discovery. NLM (Medline), 19(05)pp. 305–306,2020.
[31] Uddin, M., Mustafa, F., Rizvi, T. A., Loney, T., Al Suwaidi, H., Al-Marzouqi, A. H. H., Senok, A. C. SARS-CoV-2/COVID-19: viral genomics, epidemiology, vaccines, and therapeutic interventions. Viruses, Vol.12, pp.526,2020.
[32] V’kovski, P.; Kratzel, A.; Steiner, S.; Stalder, H.; Thiel, V. Coronavirus Biology and Replication: Implications for SARS-CoV-2. Nature Reviews Microbiology. Nature Research,Vol.19, 155-170,2021.
[33] Omotuyi, I. O.; Nash, ; Ajiboye, ; Metibemu, B. O. 3?; Oyinloye, ; Ojo, ;; Okaiyeto, ; The Disruption of SARS-CoV-2 RBD/ACE-2 Complex by Ubrogepant Is Mediated by Interface Hydration. 2020.
[34] Yi, C.; Sun, X.; Ye, J.; Ding, L.; Liu, M.; Yang, Z.; Lu, X.; Zhang, Y.; Ma, L.; Gu, W.; Qu, A.; Xu, J.; Shi, Z.; Ling, Z.; Sun, B. Key Residues of the Receptor Binding Motif in the Spike Protein of SARS-CoV-2 That Interact with ACE2 and Neutralizing Antibodies. Cellular and Molecular Immunology , Vol.17, pp,–621-630,2020.
[35] Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; Wang, X. Structure of the SARS-CoV-2 Spike Receptor-Binding Domain Bound to the ACE2 Receptor. Nature , Vol.581 , 215–220,2020.
[36] Beigel, J. H.; Tomashek, K. M.; Dodd, L. E.; Mehta, A. K.; Zingman, B. S.; Kalil, A. C.; Hohmann, E.; Chu, H. Y.; Luetkemeyer, A.; Kline, S.; Lopez de Castilla, D.; Finberg, R. W.; Dierberg, K.; Tapson, V.; Hsieh, L.; Patterson, T. F.; Paredes, R.; Sweeney, D. A.; Short, W. R.; Touloumi, G.; Lye, D. C.; Ohmagari, N.; Oh, M.; Ruiz-Palacios, G. M.; Benfield, T.; Fätkenheuer, G.; Kortepeter, M. G.; Atmar, R. L.; Creech, C. B.; Lundgren, J.; Babiker, A. G.; Pett, S.; Neaton, J. D.; Burgess, T. H.; Bonnett, T.; Green, M.; Makowski, M.; Osinusi, A.; Nayak, S.; Lane, H. C. Remdesivir for the Treatment of Covid-19 — Final Report. New England Journal of Medicine , Vol.383 (19), pp. 1813–1826,2020.
[37] Boulware, D. R.; Pullen, M. F.; Bangdiwala, A. S.; Pastick, K. A.; Lofgren, S. M.; Okafor, E. C.; Skipper, C. P.; Nascene, A. A.; Nicol, M. R.; Abassi, M.; Engen, N. W.; Cheng, M. P.; LaBar, D.; Lother, S. A.; MacKenzie, L. J.; Drobot, G.; Marten, N.; Zarychanski, R.; Kelly, L. E.; Schwartz, I. S.; McDonald, E. G.; Rajasingham, R.; Lee, T. C.; Hullsiek, K. H. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. New England Journal of Medicine 2020, Vol.383 , pp.–525. 2020.
[38] Maskin, L. P.; Olarte, G. L.; Palizas, F.; Velo, A. E.; Lurbet, M. F.; Bonelli, I.; Baredes, N. D.; Rodríguez, P. O. High Dose Dexamethasone Treatment for Acute Respiratory Distress Syndrome Secondary to COVID-19: A Structured Summary of a Study Protocol for a Randomised Controlled Trial. Trials , Vol.21 , pp.1-3,2020.
[39] Morales-Ortega, A.; Bernal-Bello, D.; Llarena-Barroso, C.; Frutos-Pérez, B.; Duarte-Millán, M. Á.; García de Viedma-García, V.; Farfán-Sedano, A. I.; Canalejo-Castrillero, E.; Ruiz-Giardín, J. M.; Ruiz-Ruiz, J.; San Martín-López, J. V. Imatinib for COVID-19: A Case Report. Clinical immunology (Orlando, Fla.) , Vol.218, 108518, 2020.
[40] Musarrat, F.; Chouljenko, V.; Dahal, A.; Nabi, R.; Chouljenko, T.; Jois, S. D.; Kousoulas, K. G. The Anti-HIV Drug Nelfinavir Mesylate (Viracept) Is a Potent Inhibitor of Cell Fusion Caused by the SARSCoV-2 Spike (S) Glycoprotein Warranting Further Evaluation as an Antiviral against COVID-19 Infections. Journal of Medical Virology , Vol.10,pp. 2087–2095, 2020.
[41] Thachil, J. The Versatile Heparin in COVID-19. Journal of Thrombosis and Haemostasis. Blackwell Publishing Ltd, pp 1020–1022, 2020.
[42] Boretti, A. Favipiravir Use for SARS CoV-2 Infection. Pharmacological Reports , Vol.72 ,pp. 1542–1552, 2020.
[43] Zhu, Z.; Lu, Z.; Xu, T.; Chen, C.; Yang, G.; Zha, T.; Lu, J.; Xue, Y. Arbidol Monotherapy Is Superior to Lopinavir/Ritonavir in Treating COVID-19. Journal of Infection ,Vol. 81 (1),pp. e21–e23,2020.
[44] Hippensteel, J. A.; Lariviere, W. B.; Colbert, J. F.; Langouët-Astrié, C. J.; Schmidt, E. P. Heparin as a Therapy for COVID-19: Current Evidence and Future Possibilities. Am J Physiol Lung Cell Mol Physiol,Vol.19,pp.211–217,2020.
[45] Cao, B.; Wang, Y.; Wen, D.; Liu, W.; Wang, J.; Fan, G.; Ruan, L.; Song, B.; Cai, Y.; Wei, M.; Li, X.; Xia, J.; Chen, N.; Xiang, J.; Yu, T.; Bai, T.; Xie, X.; Zhang, L.; Li, C.; Yuan, Y.; Chen, H.; Li, H.; Huang, H.; Tu, S.; Gong, F.; Liu, Y.; Wei, Y.; Dong, C.; Zhou, F.; Gu, X.; Xu, J.; Liu, Z.; Zhang, Y.; Li, H.; Shang, L.; Wang, K.; Li, K.; Zhou, X.; Dong, X.; Qu, Z.; Lu, S.; Hu, X.; Ruan, S.; Luo, S.; Wu, J.; Peng, L.; Cheng, F.; Pan, L.; Zou, J.; Jia, C.; Wang, J.; Liu, X.; Wang, S.; Wu, X.; Ge, Q.; He, J.; Zhan, H.; Qiu, F.; Guo, L.; Huang, C.; Jaki, T.; Hayden, F. G.; Horby, P. W.; Zhang, D.; Wang, C. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine 2020, Vol.382 , pp.1787–1799.
[46] Trott, O.; Olson, A. J. AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. Journal of Computational Chemistry , Vol.31, pp.455-461,2009.
[47] Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF Chimera - A Visualization System for Exploratory Research and Analysis. , 2021.
[48] Morris, G. M.; Ruth, H.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. Software News and Updates AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. Journal of Computational Chemistry , Vol.30 (16), 2785–2791,2009.
[49] Schwede, T.; Kopp, J.; Guex, N.; Peitsch, M. C. SWISS-MODEL: An Automated Protein Homology-Modeling Server. Nucleic Acids Research , Vol.13,pp. 3381–3385,2003.
(50) Dallakyan, S.; Olson, A. J. Small-Molecule Library Screening by Docking with PyRx. Methods in Molecular Biology Vol. 1263, pp.243–250,2015.
[51] Valdés-Tresanco, M. S.; Valdés-Tresanco, M. E.; Valiente, P. A.; Moreno, E. AMDock: A Versatile Graphical Tool for Assisting Molecular Docking with Autodock Vina and Autodock4. Biology Direct , Vol.15 (1),2020.
[52] Jász, Á.; Rák, Á.; Ladjánszki, I.; Tornai, G. J.; Cserey, G. Towards Chemically Accurate QM/MM Simulations on GPUs. Journal of Molecular Graphics and Modelling , Vol.96, pp.107536,2020.
[53] Wang, Z.; Ho, J. X.; Ruble, J. R.; Rose, J.; Rüker, F.; Ellenburg, M.; Murphy, R.; Click, J.; Soistman, E.; Wilkerson, L.; Carter, D. C. Structural Studies of Several Clinically Important Oncology Drugs in Complex with Human Serum Albumin. Biochimica et Biophysica Acta (BBA) - General Subjects Vol.1830 ,pp.5374. ,2013.
[54) Hsu, K. C.; Chen, Y. F.; Lin, S. R.; Yang, J. M. Igemdock: A Graphical Environment of Enhancing Gemdock Using Pharmacological Interactions and Post-Screening Analysis. BMC Bioinformatics , Vol.12 , pp.11, 2011.
[55] Schneidman-Duhovny, D.; Inbar, Y.; Nussinov, R.; Wolfson, H. J. PatchDock and SymmDock: Servers for Rigid and Symmetric Docking. Nucleic Acids Research , Vol.33, pp. W363-W367, 2005.
[56] Badri, P. S.; King, J. R.; Polepally, A. R.; McGovern, B. H.; Dutta, S.; Menon, R. M. Dosing Recommendations for Concomitant Medications During 3D Anti-HCV Therapy. Clinical Pharmacokinetics. Springer International Publishing , Vol. 55, pp.275–295,,2016.
[57] Dodick, D. W.; Lipton, R. B.; Ailani, J.; Lu, K.; Finnegan, M.; Trugman, J. M.; Szegedi, A. Ubrogepant for the Treatment of Migraine. New England Journal of Medicine , Vol.381 ,pp. 2230–2241, 2019.
[58] Boinpally, R.; Jakate, A.; Butler, M.; Borbridge, L.; Periclou, A. Single-Dose Pharmacokinetics and Safety of Atogepant in Adults With Hepatic Impairment: Results From an Open-Label, Phase 1 Trial. Clinical Pharmacology in Drug Development , Vol.10 , 726–733, 2021.