The virtual screening application for searching potential antiviral agents to treat COVID-19 disease
Keywords:coronavirus infection, SARS-CoV-2, Mpro protease, 6LU7, molecular docking, virtual screening, antiviral activity, [1, 2, 4]triazolo[4, 3-a]pyridine, 1, 4-оxadiazole, 3-a]quinazolin-5-ones
Aim. To provide a brief literature review regarding the structure of the human coronavirus SARS-CoV-2, the mechanism of its replication and the role of viral proteases in this process; to analyze the ability of the known antiviral agents and compounds synthesized de novo in order to bind and inhibit the coronavirus main protease using computer simulation tools.
Results and discussion. COVID-19 coronavirus has become a worldwide challenge in recent months. Taking into account the rapid spread and severity of COVID-19 among a significant part of the population there is an urgent need to develop effective medicines and appropriate treatment protocols, which, unfortunately, are not yet available. Currently, the search for molecules with an acceptable toxicity profile that are able to inhibit and/or stop coronavirus SARS-CoV-2 replication in the human body is very relevant. In this study, the virtual screening and molecular docking of both antiviral agents known and new compounds synthesized have been performed based on the structure of the main protease Mpro of SARS-CoV-2. The regularities identified during our study can be useful for searching and developing new antiviral drugs to control COVID-19 and other coronavirus infections. The analysis of the results of calculations of physicochemical characteristics of antiviral agents, as well as the determination of their binding sites with the main viral protease Mpro gives an optimistic assessment of the possibility to develop new drugs based on the structures of the known antiviral drugs or their modified analogs.
Experimental part. Based on recent studies of the crystal structure of the virus main protease Mpro in the complex with various inhibitors (Protein Data Bank http://www.rcsb.org/pdb, the structure code – 6LU7) the virtual screening and molecular docking of 100 known antiviral agents and 50 novel compounds synthesized were performed. The screening data for the in vitro antimalarial activity of the compounds synthesized were presented. The following binding and physicochemical parameters of the ligand–protein interaction for all virus main protease potential inhibitors were calculated: binding affinity score (BAS), binding energy, lipophilicity (clogP) and topological polar surface area (TPSA). The protein and ligand structures were studied using Jmol, PyMol, and Avogadro graphics software packages. The virtual screening and molecular docking, as well as the analysis of the results were performed using a LigandScout 4.4 software package. Data on the antimalarial activity of 50 compounds synthesized were obtained from the Laboratory of Microbiology, Parasitology and Hygiene of theUniversity ofAntwerp (Belgium).
Conclusions. According to the results of the virtual screening and molecular docking with protein 6LU7 it has been found that a number of the known antiviral drugs have a certain potential for their use as inhibitors of SARS-CoV-2 coronavirus main protease. Remdesivir and ritonavir substances have shown higher activity than the reference compound of the 6LU7 complex. The molecular docking of a series of compounds recently synthesized with the proven in vitro antimalarial activity has revealed that L1 – L6 compounds are promising candidates for further modification and development of new antiviral drugs to control coronavirus infection.
Xu, J.; Zhao, S.; Teng, T.; Abdalla, A. E.; Zhu, W.; Xie, L.; Wang, Y.; Guo, X. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 2020, 12, 244. https://doi.org/10.3390/v12020244.
Coronavirus disease (COVID-2019) situation reports. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports (accessed 5 May 2020).
Liu, C.; Zhou, Q.; Li, Y.; Garner, L. V.; Watkins, S. P.; Carter, L. J.; Smoot, J.; Gregg, A. C.; Daniels, A. D.; Jervey, S.; Albaiu, D. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci. 2020, 6 (3), 315–331. https://doi.org/10.1021/acscentsci.0c00272.
Fan, Y.; Zhao, K.; Shi, Z.-L.; Zhou, P. Bat Coronaviruses in China. Viruses 2019, 11, 210. https://doi.org/10.3390/v11030210.
Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; Duan, Y.; Yu, J.; Wang, L.; Yang, K.; Liu, F.; Jiang, R.; Yang, X.; You, T.; Liu, X.; Yang, X.; Bai, F.; Liu, H.; Liu, X.; Guddat, L. W.; Xu, W.; Xiao, G.; Qin, C.; Shi, Z.; Jiang, H.; Rao, Z.; Yang, H. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature 2020, 582, 289–293. https://doi.org/10.1038/s41586-020-2223-y.
Агеева, Л. В. Рецепторы ангиотензина ІІ в регуляции дифференцировки и секреторной активности мезенхимных стромальных клеток жировой ткани человека. Диссертация канд. биол. наук, Московский государственный университет имени М. В. Ломоносова, Москва, 2019.
Dinh, D. T.; Frauman, A. G.; Johnston, C. I.; Fabiani, M. E. Angiotensin receptors: distribution, signalling and function. Clinical Science 2001, 100 (5), 481–492. https://doi.org/10.1042/cs1000481.
Su, Y. C.; Anderson, D. E.; Young, B. E.; Zhu, F.; Linster, M.; Kalimuddin, S.; Low, J. G.; Yan, Z.; Jayakumar, J.; Sun, L.; Yan, G. Z.; Mendenhall, I. H.; Leo, Y.-S.; Lye, D. C.; Wang, L.-F.; Smith, G. J. Discovery of a 382-nt deletion during the early evolution of SARS-CoV-2. bioRxiv 2020, 2020.03.11.987222. https://doi.org/10.1101/2020.03.11.987222.
COVID-19: Finding the Right Fit. https://drugbank.s3-us-west-2.amazonaws.com/assets/blog/COVID-19_Web.pdf (accessed 7 May 2020).
Odynets, K. A.; Kornelyuk, A. I. Molecular aspects of organization and expression of SARS-CoV coronavirus genome. Biopolym. Cell 2003, 19 (5), 414–431. http://dx.doi.org/10.7124/bc.00066F.
Zhang, L.; Lin, D.; Sun, X.; Curth, U.; Drosten, C.; Sauerhering, L.; Becker, S.; Rox, K.; Hilgenfeld, R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 2020, 368 (6489), 409–412. https://doi.org/10.1126/science.abb3405.
Zhang, L.; Lin, D.; Hilgenfeld, R. Crystal structure of the complex resulting from the reaction between the SARS-CoV main protease and tert-butyl (1-((S)-3-cyclohexyl-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate. PDB ID 6Y7M 2020. http://dx.doi.org/10.2210/pdb6Y7M/pdb.
Khaerunnisa, S.; Kurniawan, H.; Awaluddin, R.; Suhartati, S.; Soetjipto, S. Potential Inhibitor of COVID-19 Main Protease (Mpro) From Several Medicinal Plant Compounds by Molecular Docking Study. Preprints 2020, 2020030226. https://doi.org/10.20944/preprints202003.0226.v1.
Alamri, M. A.; Tahir ul Qamar, M.; Alqahtani, S. M. Pharmacoinformatics and Molecular Dynamic Simulation Studies Reveal Potential Inhibitors of SARS-CoV-2 Main Protease 3CLpro. Preprints 2020, 2020020308. https://doi.org/10.20944/preprints202002.0308.v1.
Berman, H.; Henrick, K.; Nakamura, H. Announcing the worldwide Protein Data Bank. Nat. Str. Biol. 2003, 10 (12), 980-980. https://doi.org/10.1038/nsb1203-980.
Jmol: an open-source Java viewer for chemical structures in 3D; http://www.jmol.org/.
DeLano, W. L. Pymol: An open-source molecular graphics tool. CCP4 Newsletter On Protein Crystallography 2002, 40, 82–92.
Avogadro: an open-source molecular builder and visualization tool, 1.XX; http://avogadro.cc/.
Wolber, G.; Dornhofer, A. A.; Langer, T. Efficient overlay of small organic molecules using 3D pharmacophores. J. Comput.-Aided Mol. Des. 2006, 20 (12), 773–788. https://doi.org/10.1007/s10822-006-9078-7.
Rutkowska, E.; Pajak, K.; Jóźwiak, K. Lipophilicity – methods of determination and its role in medicinal chemistry. Acta Pol. Pharm. 2013, 70 (1), 3–18.
Clark, D. E. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. J. Pharm. Sci. 1999, 88 (8), 807–814. https://doi.org/10.1021/js9804011.
Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 2001, 46 (1–3), 3–26. https://doi.org/10.1016/S0169-409X(00)00129-0.
Giordanetto, F.; Kihlberg, J. Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties? J. Med. Chem. 2014, 57 (2), 278–295. https://doi.org/10.1021/jm400887j.
Chang, R.; Sun, W. Repositioning Chloroquine as Ideal Antiviral Prophylactic against COVID-19 – Time is Now. Preprints 2020, 2020030279. https://doi.org/10.20944/preprints202003.0279.v1.
Karpina, V. R.; Kovalenko, S. M.; Zaremba, O. V.; Silin, O. V.; Ivanov, V. V.; Kovalenko, S. S.; Langer, T. The search for potential inhibitors of protein kinase Pim-1 among new amides of 1,2,4-triazolo[4,3-a]pyridine-3-metanamin with the 1,2,4-oxadiazol cycle in position 7 and 8. J. Org. Pharm. Chem. 2019, 17 (3(67)), 5–14. https://doi.org/10.24959/ophcj.19.174807.
Nechayev, M. A.; Gorobets, N. Y.; Shishkina, S. V.; Shishkin, O. V.; Kovalenko, S. M. Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: the synthesis of 7-amino-6-azaindoles. Tetrahedron 2015, 71 (8), 1311–1321. https://doi.org/10.1016/j.tet.2014.12.057.
Zaremba, O. V.; Gorobets, N. Y.; Kovalenko, S. S.; Drushlyak, O. G.; Grevtsov, O. Y.; Kovalenko, S. M. Facile one-pot synthesis of the pyrazolo[1,5-a]-pyrazine scaffold. Chem. Heterocycl. Compd. 2013, 49 (6), 915–921. https://doi.org/10.1007/s10593-013-1326-x.
Nechayev, M. A.; Gorobets, N. Y.; Borisov, A. V.; Kovalenko, S. M.; Tolmachev, A. A. The synthesis of low molecular weight pyrrolo[2,3-c]pyridine-7-one scaffold. Mol. Diversity 2012, 16 (4), 749–757. https://doi.org/10.1007/s11030-012-9410-1.
Nwaka, S.; Ramirez, B.; Brun, R.; Maes, L.; Douglas, F.; Ridley, R. Advancing Drug Innovation for Neglected Diseases – Criteria for Lead Progression. PLoS Neglected Trop. Dis. 2009, 3 (8), e440. https://doi.org/10.1371/journal.pntd.0000440.
Danylchenko, S. Y.; Kovalenko, S. S.; Drushlyak, O. G.; Kovalenko, S. M.; Maes, L. [1,2,4]triazolo[4,3-a]quinazolin-5-one derivatives as antimalarial agents. Ukr. Biopharm. J. 2016, 1 (42), 78–83. https://doi.org/10.24959/ubphj.16.16.
Warren, G. L.; Andrews, C. W.; Capelli, A.-M.; Clarke, B.; LaLonde, J.; Lambert, M. H.; Lindvall, M.; Nevins, N.; Semus, S. F.; Senger, S.; Tedesco, G.; Wall, I. D.; Woolven, J. M.; Peishoff, C. E.; Head, M. S. A Critical Assessment of Docking Programs and Scoring Functions. J. Med. Chem. 2006, 49 (20), 5912–5931. https://doi.org/10.1021/jm050362n.
Copyright (c) 2020 National University of Pharmacy
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors publishing their works in the Journal of Organic and Pharmaceutical Chemistry agree with the following terms:
1. Authors retain copyright and grant the journal the right of the first publication of the work under Creative Commons Attribution License allowing everyone to distribute and re-use the published material if proper citation of the original publication is given.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal’s published version of the work (e.g., post it to an institutional repository or publish it in a book) providing proper citation of the original publication.
3. Authors are permitted and encouraged to post their work online (e.g. in institutional repositories or on authors’ personal websites) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (see The Effect of Open Access).