Computational medicinal chemistry role in clinical pharmacy education: Ingavirin for coronavirus disease 2019 (COVID-19) discovery model

Main Article Content

Keywords

Coronavirus disease (COVID-19), Novel coronavirus (nCoV), Ingavirin, Angiotensin-converting enzyme 2 (ACE2), Practitioner, Molecular docking

Abstract

Objective: Given the major shift to patient-directed education, novel coronavirus (nCoV) provides a live example on how medicinal chemistry could be a key science to teach pharmacy students. In this paper, students and clinical pharmacy practitioners will find a stepwise primer on identifying new potential nCoV treatments mechanistically modulated through angiotensin-converting enzyme 2 (ACE2). Methods: First, we identified the maximum common pharmacophore between carnosine and melatonin as background ACE2 inhibitors. Second, we performed a similarity search to spot out structures containing the pharmacophore. Third, molinspiration bioactivity scoring enabled us to promote one of the newly identified molecules as the best next candidate for nCoV. Preliminary docking in SwissDock and visualization through University of California San Francisco (UCSF) chimera made it possible to qualify one of them for further detailed docking and experimental validation. Results: Ingavirin had the best docking results with full fitness of −3347.15 kcal/mol and estimated ΔG of −8.53 kcal/mol compared with melatonin (−6.57 kcal/mol) and carnosine (−6.29 kcal/mol). UCSF chimera showed viral spike protein elements binding to ACE2 retained in the best ingavirin pose in SwissDock at 1.75 Angstroms. Conclusion: Ingavirin has a promising inhibitory potential to host (ACE2 and nCoV spike protein) recognition, and hence could offer the next best mitigating effect against the current coronavirus disease (COVID-19) pandemic.

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References

1. Stepensky D. Prediction of Drug Disposition on the Basis of its Chemical Structure. Clin Pharm. 2013;52(6):415-431. https://doi.org/10.1007/s40262-013-0042-0
2. Al-Taweel D, Al-Haqan A, Bajis D, et al. Multidisciplinary academic perspectives during the COVID-19 pandemic. Int J Health Plann Manage. 2020;35(6):1295-1301. https://doi.org/10.1002/hpm.3032
3. Amawi H, Abu Deiab GI, Aljabali AAA, et al. COVID-19 pandemic: An overview of epidemiology, pathogenesis, diagnostics and potential vaccines and therapeutics. Ther Deliv. 2020;11(4):245-268. https://doi.org/10.4155/tde-2020-0035
4. Jakupi A, Jakupi AB. Pharmacy practice architecture challenges in handling COVID-19 pandemic - sharing experience from a Kosovo pharmacy practice. Pharm Pract (Granada). 2021;19(4):2597. https://doi.org/10.18549/PharmPract.2021.4.2597
5. World Health Organization. Rolling Updates on Coronavirus Disease (COVID-19). 31 December 2019. Available online: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen (accessed on 29 December 2020).
6. Worldometer. COVID-19 Coronavirus Pandemic. 21 September 2020. Available online: https://www.worldometers.info/coronavirus/ (accessed on 14 September 2022).
7. Urick BY, Meggs EV. Towards a Greater Professional Standing: Evolution of Pharmacy Practice and Education, 1920-2020.Pharmacy (Basel). 2019;7(3):98. https://doi.org/10.3390/pharmacy7030098
8. Merz KM, De Fabritis G, Wei G. Generative Models for Molecular Design. J Chem Inf Model. 2020;60(12):5635-5636. https://doi.org/10.1021/acs.jcim.0c01388
9. Mulholland AJ, Amaro RE. COVID19 - Computational Chemists Meet the Moment. J Chem Inf Model. 2020;60(12):5724-726.https://doi.org/10.1021/acs.jcim.0c01395
10. Haskell AR, Benedict LK. The universal Doctor of Pharmacy degree. Am J Pharm Educ. 1975;39:425-427.
11. Hepler CD. The third wave in pharmaceutical education: The clinical movement. Am J Pharm Educ. 1987;51(4):369-385.
12. Fernandes, João Paulo S. The Importance of Medicinal Chemistry Knowledge in the Clinical Pharmacist’s Education. Am J
Pharma Education. 2018;82(2):6083. https://doi.org/10.5688/ajpe6083
13. Tsutsumi LS, Owusu YB, Hurdle JG, et al. Progress in the discovery of treatments for C. difficile infection: A clinical and medicinal chemistry review. Curr Top Med Chem. 2014;14(1):152-175. https://doi.org/10.2174/1568026613666131113154753
14. Feitosa EL, Júnior FTDSS, Nery Neto JAO, et al. COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor. Int J Med Sci. 2020;17(14):2133-2146. https://doi.org/10.7150/ijms.48053
15. Giménez VM, Prado N, Diez E, et al. New proposal involving nanoformulated melatonin targeted to the mitochondria as a potential COVID-19 treatment. Nanomedicine (Lond). 2020;15(29):2819-2821. https://doi.org/10.2217/nnm-2020-0371
16. Saadah LM, Deiab GIA, Al-Balas Q, et al. Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein. Molecules. 2020;25(23):5605. https://doi.org/10.3390/molecules25235605
17. Srinivasan V, Mohamed M, Kato H. Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent Pat Endocr Metab Immune Drug Discov. 2012;6(1):30-9. https://doi.org/10.2174/187221412799015317
18. Tanaka KI, Kawahara M. Carnosine and Lung Disease. Curr Med Chem. 2020;27(11):1714-1725. https://doi.org/10.2174/092 9867326666190712140545
19. Rodríguez-Rubio M, Figueira JC, Acuña-Castroviejo D, et al. A phase II, single-center, double-blind, randomized placebocontrolled trial to explore the efficacy and safety of intravenous melatonin in patients with COVID-19 admitted to the intensivecare unit (MelCOVID study): a structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21(1):699.https://doi.org/10.1186/s13063-020-04632-4
20. Ziaei A, Davoodian P, Dadvand H, et al. Evaluation of the efficacy and safety of Melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial. Trials. 2020;21(1):882. https://doi. org/10.1186/s13063-020-04737-w
21. Torres JE, Baldiris R, Vivas-Reyes R. Design of Angiotensin-converting Enzyme 2 (ACE2) Inhibitors by Virtual Lead Optimization and Screening. J Chin Chem Soc. 2012;59:1394-1400. https://doi.org/10.1002/jccs.201200079
22. Dales N, Gould A, Brown J, et al. Substrate-Based Design of the First Class of Angiotensin-Converting Enzyme-Related Carboxypeptidase (ACE2) Inhibitors. J Am Chem Soc. 2002;124(40):11852. https://doi.org/10.1021/ja0277226
23. Fara DC, Oprea TI. Section III: Cheminformatics—Basics: Molecular Similarity (or Diversity). University of New Mexico. http://datascience.unm.edu/biomed505/Course/Cheminformatics/basic/similarity_diversity/similarity_diversity.htm (accessed on 25 July 2020).
24. Lee JK. Statistical Bioinformatics: A Guide for Life and Biomedical Science Researchers; Wiley-Blackwell: Hoboken, NJ, USA. 2010.
25. Baldi P, Benz RW. BLASTing small molecules--statistics and extreme statistics of chemical similarity scores. Bioinformatics2008;24(13):357-365. https://doi.org/10.1093/bioinformatics/btn187
26. Jarrahpour A, Fathi J, Mostafa M, et al. Petra, Osiris and Molinspiration (POM) Together as a Successful Support in Drug Design:Antibacterial Activity and Biopharmaceutical Characterization of Some Azo Schiff Bases. Med Chem Res. 2012;21(8):1984-1990. https://doi.org/10.1007/s00044-011-9723-0
27. Backman TWH, Cao Y, Girke T. ChemMine tools: An online service for analyzing and clustering small molecules. Nucleic Acids Res. 2011;39(Suppl. 2):W486-W491. https://doi.org/10.1093/nar/gkr320
28. Kong Q, Wu Y, Gu Y, et al. Analysis of the molecular mechanism of Pudilan (PDL) treatment for COVID-19 by network pharmacology tools. Biomed Pharmacother. 2020;128:110316. https://doi.org/10.1016/j.biopha.2020.110316
29. Wirth M, Zoete V, Michielin O, et al. SwissBioisostere: a database of molecular replacements for ligand design, Nucleic Acids Research. 2013;41(Database issue):D1137-1143. https://doi.org/10.1093/nar/gks1059
30. Malík I, Kovac G, Padrtova T, et al. Ingavirin might be a promising agent to combat Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2). Ceska Slov Farm. 2020;69(3):107-111.
31. Johansen MD, Irving A, Montagutelli X, et al. Animal and translational models of SARS-CoV-2 infection and COVID-19. MucosalImmunol. 2020;13(6):877-891. https://doi.org/10.1038/s41385-020-00340-z
32. Khelfaoui H, Harkati D, Saleh BA. Molecular docking, molecular dynamics simulations and reactivity, studies on approved drugslibrary targeting ACE2 and SARS-CoV-2 binding with ACE2. J Biomol Struct Dyn. 2021;39(18):7246-7262. https://doi.org/10.1080/07391102.2020.1803967
33. Chikhale RV, Gurav SS, Patil RB, et al. Sars-cov-2 host entry and replication inhibitors from Indian ginseng: An in-silico approach.J Biomol Struct Dyn. 2021;39(12):4510-4521. https://doi.org/10.1080/07391102.2020.1778539
34. Malík I, Kovac G, Padrtova T, et al. Ingavirin might be a promising agent to combat Severe Acute Respiratory Coronavirus 2(SARS-CoV-2). Ceska Slov Farm. 2020;69(3):107-111.
35. Starr TN, Greaney AI, Hilton SK, et al. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints onfolding and ACE2 binding. Cell. 2020;182(5):1295-1310.e20. https://doi.org/10.1016/j.cell.2020.08.012
36. Chowdhury R, Boorla VS, Maranas CD. Computational biophysical characterization of the SARS-CoV-2 spike protein binding withthe ACE2 receptor and implications for infectivity. Comput Struct Biotechnol J. 2020;18:2573-2582. https://doi.org/10.1016/j.
csbj.2020.09.019
37. Chan KK, Dorosky D, Sharma P, et al. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2.Science. 2020;369(6508):1261-1265. https://doi.org/10.1126/science.abc0870

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