Molecular interactions of some phenolics with 2019-nCoV and related pathway elements

Abstract

As of June 2021, the novel coronavirus disease (SARS-CoV-2) resulted in 180 million cases worldwide and resulted in the death of approximately 4 million people. However, an effective pharmaceutical with low side effects that can be used in the treatment of SARS-CoV-2 infection has not been developed yet. The aim of this computational study was to analyze the interactions of twenty-two hydroxycinnamic acid and hydroxybenzoic acid derivatives with the SARS-CoV-2 receptor binding domain (RBD) and host organism's proteases, transmembrane serine protease 2 (TMPRSS2), and cathepsin B and L (CatB/L). According to the RBCI analysis, the ligands with the highest affinity against 4 enzymes in the molecular docking study were determined as 1-caffeoyl-β-D-glucose, rosmarinic acid, 3-p-coumaroylquinic acid and chlorogenic acid. It has also been observed that these compounds interacted more strongly with spike RBD, CatB and CatL enzymes. Although the top-ranked ligand, 1-caffeoyl-β-D-glucose, violated the drug-likeness criteria at 1 point (NH or OH>5) and ADMET in terms of AMES toxicity, the second top-ranked ligand rosmarinic acid neither violated drug-likeness nor exhibited incompatibility in terms of ADMET. In conclusion, with its anti-inflammatory properties, rosmarinic acid can be considered and further investigated as a plant-based pharmaceutical that can offer a treatment option in SARS-CoV-2 infection. However, our findings should be supported by additional in vitro and in vivo studies.

Keywords

• SARS-CoV-2
• Molecular docking
• Rosmarinic acid
• Spike glycoprotein
• TMPRSS2
• Cathepsins

References

1. Adem, Ş., Eyupoglu, V., Sarfraz, I., Rasul, A., Zahoor, A.F., Ali, M., Abdalla, M., Ibrahim, I.M., & Elfiky, A.A. (2021). Caffeic acid derivatives (CAFDs) as inhibitors of SARS-CoV-2: CAFDs-based functional foods as a potential alternative approach to combat COVID-19. Phytomedicine, 85, 153310.
2. Andersen, K.G., Rambaut, A., Lipkin, W.I., Holmes, E.C., & Garry, R.F. (2020). The proximal origin of SARS-CoV-2. Nature Medicine, 26, 450–452.
3. Cano-Avendaño, B.A., Carmona-Hernandez, J.C., Rodriguez, R.E., Taborda-Ocampo, G., & González-Correa, C.H. (2021). Chemical properties of polyphenols: a reviewfocusedonanti-inflammatory and anti-viral medical application. Biomedicine, 41(1), 3-8.
4. Chavez, J.H., Leal, P.C., Yunes, R.A., Nunes, R.J., Barardi, C.R., Pinto, A.R., Simoes, C.M., & Zanetti, C.R. (2006). Evaluation of antiviral activity of phenolic compounds and derivatives against rabies virus. Veterinary Microbiology, 116(1-3), 53-59.
5. Coban, M.A., Morrison, J., Maharjan, S., Hernandez Medina, D.H., Li, W., Zhang, Y.S., Freeman, W.D., Radisky, E.S., Le Roch, K.G., & Weisend, C.M. (2021). Attacking COVID-19 progression using multi-drug therapy for synergetic target engagement. Biomolecules, 11(6), 787.
6. Dong, Y., Tang, D., Zhang, N., Li, Y., Zhang, C., Li, L., & Li, M. (2013). Phytochemicals and biological studies of plants in genus Hedysarum. Chemistry Central Journal, 7(1), 1-13.
7. Fu, Y., Cheng, Y., & Wu, Y. (2020). Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools. Virologica Sinica, 35(3), 266-271.
8. Georgousaki, K., Tsafantakis, N., Gumeni, S., Lambrinidis, G., González-Menéndez, V., Tormo, J.R., Genilloud, O., Trougakos, I.P., & Fokialakis, N. (2020). Biological evaluation and in silico study of benzoic acid derivatives from Bjerkandera adusta targeting proteostasis network modules. Molecules, 25(3), 666.

9. Guan, M., Guo, L., Ma, H., Wu, H., & Fan, X. (2021). Network pharmacology and molecular docking suggest the mechanism for biological activity of rosmarinic acid. Evidence-Based Complementary and Alternative Medicine, 2021.
10. Guler, H.I., Fulya, A., Zehra, C., Yakup, K., Belduz, A.O., Canakci, S., & Kolayli, S. (2021). Targeting CoV-2 Spike RBD and ACE-2 Interaction with Flavonoids of Anatolian Propolis by in silico and in vitro Studies in terms of possible COVID-19 therapeutics. BioRxiv, https://doi.org/10.1101/2021.02.22.432207.
11. Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.-H., & Nitsche, A. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181(2), 271-280.
12. Huang, I.-C., Bosch, B.J., Li, F., Li, W., Lee, K.H., Ghiran, S., Vasilieva, N., Dermody, T.S., Harrison, S.C., & Dormitzer, P.R. (2006). SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. Journal of Biological Chemistry, 281(6), 3198-3203.
13. Jahan, I., & Onay, A. (2020). Potentials of plant-based substance to inhabit and probable cure for the COVID-19. Turkish Journal of Biology, 44(3), 228-241.
14. Kumar Verma, A., Kumar, V., Singh, S., Goswami, B.C., Camps, I., Sekar, A., Yoon, S., & Lee, K.W. (2021). Repurposing potential of Ayurvedic medicinal plants derived active principles against SARS-CoV-2 associated target proteins revealed by molecular docking, molecular dynamics and MM-PBSA studies. Biomedicine & Pharmacotherapy, 137, 111356.
15. Lee, J., Jung, E., Kim, Y., Lee, J., Park, J., Hong, S., Hyun, C.-G., Park, D., & Kim, Y.S. (2006). Rosmarinic acid as a downstream inhibitor of IKK-β in TNF-α-induced upregulation of CCL11 and CCR3. British Journal of Pharmacology, 148(3), 366-375.
16. Letko, M., Marzi, A., & Munster, V. (2020). Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nature Microbiology, 5(4), 562-569.
17. Li, F., Li, W., Farzan, M., & Harrison, S.C. (2005). Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science, 309(5742), 1864-1868.
18. Li, W., Moore, M.J., Vasilieva, N., Sui, J., Wong, S.K., Berne, M.A., Somasundaran, M., Sullivan, J.L., Luzuriaga, K., & Greenough, T.C. (2003). Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 426(6965), 450-454.
19. Luan, J., Lu, Y., Jin, X., & Zhang, L. (2020). Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection. Biochemical and Biophysical Research Communications, 526(1), 165-169.
20. Maalik, A., Bukhari, S.M., Zaidi, A., Shah, K.H., & Khan, F.A. (2016). Chlorogenic acid: a pharmacologically potent molecule. Acta Poloniae Pharmaceutica, 73(4), 851-854.
21. Meng, X.-Y., Zhang, H.-X., Mezei, M., & Cui, M. (2011). Molecular docking: a powerful approach for structure-based drug discovery. Current Computer-Aided Drug Design, 7(2), 146-157.
22. Mohammad, A., Alshawaf, E., Marafie, S.K., Abu-Farha, M., Al-Mulla, F., & Abubaker, J. (2021). Molecular Simulation-Based Investigation of Highly Potent Natural Products to Abrogate Formation of the nsp10-nsp16 Complex of SARS-CoV-2. Biomolecules, 11(4), https://doi.org/10.3390/biom11040573.
23. Nam, H.-H., Kim, J.S., Lee, J., Seo, Y.H., Kim, H.S., Ryu, S.M., Choi, G., Moon, B.C., & Lee, A.Y. (2020). Pharmacological Effects of Agastache rugosa against Gastritis Using a Network Pharmacology Approach. Biomolecules, 10(9), 1298.
24. Piccolella, S., Crescente, G., Faramarzi, S., Formato, M., Pecoraro, M.T., & Pacifico, S. (2020). Polyphenols vs. coronaviruses: how far has research moved forward? Molecules, 25(18), 4103.
25. Ruibo, L., Narita, R., Nishimura, H., Marumoto, S., Yamamoto, S., Ouda, R., Yatagai, M., Fujita, T., & Watanabe, T. (2017). Antiviral Activity of Phenolic Derivatives in Pyroligneous Acid from Hardwood, Softwood, and Bamboo. Sustainable Chemistry & Engineering, 6(1), 119-126.
26. Srivastava, N., Garg, P., Srivastava, P., & Seth, P.K. (2021). A molecular dynamics simulation study of the ACE2 receptor with screened natural inhibitors to identify novel drug candidate against COVID-19. PeerJ, 9, e11171.
27. Sudhan, D.R., & Siemann, D.W. (2015). Cathepsin L targeting in cancer treatment. Pharmacology & Therapeutics, 155, 105-116.
28. Surucic, R., Tubic, B., Stojiljkovic, M.P., Djuric, D.M., Travar, M., Grabez, M., Savikin, K., & Skrbic, R. (2021). Computational study of pomegranate peel extract polyphenols as potential inhibitors of SARS-CoV-2 virus internalization. Molecular and Cellular Biochemistry, 476(2), 1179-1193.
29. Taguchi, R., Hatayama, K., Takahashi, T., Hayashi, T., Sato, Y., Sato, D., Ohta, K., Nakano, H., Seki, C., & Endo, Y. (2017). Structure–activity relations of rosmarinic acid derivatives for the amyloid β aggregation inhibition and antioxidant properties. European Journal of Medicinal Chemistry, 138, 1066-1075.
30. Worldometers.info. (2021). COVID-19 Coronavirus Pandemic Retrieved 20.06.2021
31. Wu, A., Peng, Y., Huang, B., Ding, X., Wang, X., Niu, P., Meng, J., Zhu, Z., Zhang, Z., & Wang, J. (2020). Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host & Microbe, 27, 325-328.
32. Wu, F., Zhao, S., Yu, B., Chen, Y.-M., Wang, W., Song, Z.-G., Hu, Y., Tao, Z.-W., Tian, J.-H., & Pei, Y.-Y. (2020). A new coronavirus associated with human respiratory disease in China. Nature, 579(7798), 265-269.
33. Wu, Y.H., Zhang, B.Y., Qiu, L.P., Guan, R.F., Ye, Z.H., & Yu, X.P. (2017). Structure properties and mechanisms of action of naturally originated phenolic acids and their derivatives against human viral infections. Current Medicinal Chemistry, 24(38), 4279-4302.
34. Zakaryan, H., Arabyan, E., Oo, A., & Zandi, K. (2017). Flavonoids: promising natural compounds against viral infections. Archives of Virology, 162(9), 2539-2551.
35. Zhou, P., Yang, X.-L., Wang, X.-G., Hu, B., Zhang, L., Zhang, W., Si, H.-R., Zhu, Y., Li, B., & Huang, C.-L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270-273.
36. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., & Lu, R. (2020). A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine, 382, 727-733.
37. Camacho, C., Coulouris, G., Avagyan, V., Ma, N., Papadopoulos, J., Bealer, K., & Madden, T.L. (2009). BLAST+: architecture and applications. BMC Bioinformatics, 10(1), 421.
38. Chandran, U., Mehendale, N., Tillu, G., & Patwardhan, B. (2015). Network Pharmacology of Ayurveda Formulation Triphala with Special Reference to Anti-Cancer Property. Combinatorial Chemistry & High Throughput Screening, 18(9), 846-854.
39. Colovos, C., & Yeates, T.O. (1993). Verification of protein structures: patterns of nonbonded atomic interactions. Protein Science, 2(9), 1511-1519.
40. Daina, A., Michielin, O., & Zoete, V. (2019). SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research, 47(W1), W357-W364.
41. Istifli, E.S., Netz, P.A., Sihoglu Tepe, A., Husunet, M.T., Sarikurkcu, C., & Tepe, B. (2020). In silico analysis of the interactions of certain flavonoids with the receptor-binding domain of 2019 novel coronavirus and cellular proteases and their pharmacokinetic properties. Journal of Biomolecular Structure and Dynamics, https://doi.org/10.1080/07391102.2020.1840444.
42. Laskowski, R.A., Rullmannn, J.A., MacArthur, M.W., Kaptein, R., & Thornton, J.M. (1996). AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. Journal of Biomolecular NMR, 8(4), 477-486.
43. Malde, A.K., Zuo, L., Breeze, M., Stroet, M., Poger, D., Nair, P.C., Oostenbrink, C., & Mark, A.E. (2011). An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0. Journal of Chemical Theory and Computation, 7(12), 4026-4037.
44. Pedretti, A., Villa, L., & Vistoli, G. (2004). VEGA–an open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming. Journal of Computer-Aided Molecular Design, 18(3), 167-173.
45. Pires, D.E., Blundell, T.L., & Ascher, D.B. (2015). pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. Journal of Medicinal Chemistry, 58(9), 4066-4072.
46. Remmert, M., Biegert, A., Hauser, A., & Söding, J. (2012). HHblits: lightning-fast iterative protein sequence searching by HMM-HMM alignment. Nature Methods, 9(2), 173-175.
47. Sanner, M.F. (1999). Python: a programming language for software integration and development. Journal of Molecular Graphics and Modelling, 17(1), 57-61.
48. Sharma, S. (1995). Applied multivariate techniques. New York, United States: John Wiley & Sons, Inc.