Activity profiling of natural and synthetic SARS-CoV-2 inhibitors Emmanuel Ohaekenyem and Chukwuebuka Onyema Department of Pure and Industrial Chemistry, Nnamdi Azikiwe University Awka, Nigeria COVID-19, the global pandemic caused by SARS-Corona virus 2 (SARS-CoV-2), is currently ravaging the World with various efforts charged at finding therapeutic drug targets for this novel virus. The identification of COVID-19 main protease (Mpro) has opened the possibility of testing new families of inhibitors as potential anti-coronaviral drugs. Protein-drug interaction is of pivotal importance to understanding the structural features essential for any ligand affinity. This study evaluated the efficacy of an isolated bioactive plant compound and synthetic tetraazamacrocycles against COVID-19 Mpro by molecular docking. Molecular docking investigations were performed by using PyRx, Auto Dock vina and Discovery Studio (DS) to analyze the inhibition probability of these compounds against COVID-19. COVID-19 Mpro (PDB ID: 6LU7: Resolution 2.16 Å) was docked with 1 flavonoid and 3 tetra aza-macrocyclic compounds comparatively with known anti-viral drugs (Remdesivir (REMD) and Nelfinavir (NELF)) and hydroxychloroquine (HCQ). Docking studies showed Jicvel 2 interacting with 5 residues having the highest binding affinity of -9.4 Kcal/mol, followed by Civel with 5 residue interactions and binding affinity value of -9.4 Kcal/mol, Jicvel 1 has 5 interactions with a binding affinity of -9.3 Kcal/mol, and Siam1 has 6 interactions with a binding energy of -7.8 Kcal/mol. All the docked potential drugs have binding energies higher than the reference drugs HCQ and REMD, connoting greater activity except NELF whose value is only lower than the 3 macrocycles (Jicvel 1 and 2, and Civel). They are bound through hydrogen bonds, and arene-anion and arene-cation interactions. The trend of binding affinity shows JICVEL2 (-9.4kcal/mol) =Civel (-9.4 kcal/mol) >; JICVEL1 (-9.3 kcal/mol) >; NELF (-8.7 kcal/mol) >; Siamone (-8.8 kcal/mol) >; HCQ (-7.2 kcal/mol)>;REMD (-6.2 kcal/mol) while the number of interactions show REMD >;JICVEL1=HCQ >; Siamone >; NELF >; JICVEL2 >; Civel. This study, hence, validates the activity of HCQ against COVID-19 and provides a foundation for advanced experimental research, to evaluate the real pharmaceutical potentials of these compounds, toward finding a cure for COVID-19. References 1. Otrompke, J. (2014). Investigating treatment strategies for the Middle East respiratory syndromecoronavirus, Pharm J ;293:7833. doi: 10.1211/PJ.2014.20066890 2. World Health Organization. 2004. SARS (Severe Acute Respiratory Syndrome) Available at: https://www.who.int/ith/ diseases/sars/en/ (accessed April 16, 2020) 3. World Health Organization. 2019. MERS Monthly summary, November 2019 Available at: https://www.who.int/emergencies/ mers-cov/en/ (accessed April 16, 2020) 4. Centers for Disease Control and Prevention. 2017. SARS Basics Fact SheetAvailable at: https://www.cdc.gov/sars/about/fs- sars.html (accessed April 16, 2020) 5. Ren, L.L., Wang, Y.M., Wu, Z.Q., Xiang, Z.C., Guo, L., Xu, T., et al. (2020). Identification of a novelcoronavirus causing severe pneumonia in humans: a descriptive study, Chinese Medical Journal , 10.1097/CM9.0000000000000722 6. Huang, C. Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, The Lancet , 395(10223), 497-506 7. Wang, W., Tang, J., Wei, F., (2020). Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan, China , J. Med. Virol. , 92 (4), 441-447, doi: 10.1002/jmv.25689
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