Comparison of clinically approved molecules on SARS-CoV-2 drug target proteins: a molecular docking study

The new type of coronavirus, SARS-CoV-2 has affected more than 22.6 million people worldwide. Since the first day the virus was spotted in Wuhan, China, numerous drug design studies have been conducted all over the globe. Most of these studies target the receptor-binding domain of spike protein of SARS-CoV-2, which is known to bind to the human ACE2 receptor and SARS-CoV-2 main protease, vital for the virus’ replication. However, there might be a third target, human furin protease, which cleaves the virus’ S1-S2 domains playing an active role in its entry into the host cell. In this study, we docked five clinically used drug molecules, favipiravir, hydroxychloroquine, remdesivir, lopinavir, and ritonavir onto three target proteins, the receptor-binding domain of SARS-CoV-2 spike protein, SARS-CoV-2 main protease, and human furin protease. Results of molecular docking simulations revealed that human furin protease might be targeted by COVID-19. Remdesivir, a nucleic acid derivative, strongly bound to the active site of this protease, suggesting that this molecule can be used as a template for designing novel furin protease inhibitors to fight against the disease. Protein-drug interactions revealed in this study at the molecular level, can pave the way for better drug design for each specific target.

Keywords:

SARS-CoV-2, COVID-19, furin protease remdesivir, molecular docking,

PDF

___

1. Fung TS, Liu DX. Human coronavirus: host-pathogen interaction. Annual Reviews of Microbiology 2019; 73: 529-557.
2. Wu C, Zheng M, Yang Y, et al. Furin: A Potential Therapeutic Target for COVID-19. iScience. 2020; 23 (10):101642. doi:10.1016/j.isci.2020.101642
3. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181 (2): 281-292.
4. Dhama K, Sharun K, Tiwari R, Dadar M, Malik YS et al. COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics. Human Vaccines & Immunotherapeutics 2020; 1-7. doi:10.1080/21645515.2020.1735227
5. Zhang L, Lin D, Sun X, Curth U, Drosten C et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 2020; 368 (6489): 409-412.
6. Liu J, Cao R, Xu M, Wang X, Zhang H et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 2020; 6: 16-19.
7. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends 2020; 14 (1): 72-73.
8. Wang M, Cao R, Zhang L, Yang X, Liu J et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020; 30 (3): 269-271.
9. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical Infectious Diseases 2020; 71 (15) :732-739. doi:10.1093/cid/ciaa237
10. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discoveries & Therapeutics 2020; 14 (1): 58-60.
11. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP et al.Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio 2018; 9 (2): e00221-18.
12. Brown AJ, Won JJ, Graham RL, Dinnon KH, Sims AC et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Research 2019, 169: 104541-104550.
13. Ko WC, Rolain JM, Lee NY, Chen PL, Huang CT et al. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. International Journal of Antimicrobial Agents 2020; 55 (4): 105933-105935.
14. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59 (3): 252-256.
15. Chen F, Chan KH, Jiang Y, Kao RY, Lu HT et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. Journal of Clinical Virology 2004; 31 (1): 69-75.
16. Liu X, Wang XJ. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. Journal of Genetics and Genomics 2020; 47 (2): 119-121.
17. Dahms SO, Arciniega M, Steinmetzer T, Huber R, Than ME. Structure of unliganded furin. Proceedings of the National Academy of Sciences 2016; 113 (40): 11196-11201.
18. Jin Z, Du X, Xu Y, Deng Y, Liu M et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature 2020; 582: 289-293.
19. Wang Q, Zhang Y, Wu L, Niu S, Song C, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 2020; 181:894-904.e9.
20. Morris GM, Huey R, Lindstrom W, Sanner, MF, Belew RK et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry 2009; 30 (16): 2785-2791.
21. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM et al. UCSF Chimera--a visualization system for exploratory research and analysis. Journal of Computational Chemistry2004; 25 (13): 1605-1612.
22. Şahin K, Durdağı S. Combined ligand and structure-based virtual screening approaches for identification of novel AChE inhibitors. Turkish Journal of Chemistry 2020; 44: 574-588.
23. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry 2010; 31 (2): 455-461.
24. Humphrey W, Dalke A, Schulten K. VMD: Visual molecular dynamics. Journal of Molecular Graphics 1996; 14 (1): 33-38.