Exploration of inhibitory action of Azo imidazole derivatives against COVID-19 main protease (Mpro): A computational study

doi:10.1016/j.molstruc.2020.129178

. 2021 Jan 15:1224:129178.

doi: 10.1016/j.molstruc.2020.129178. Epub 2020 Aug 31.

Exploration of inhibitory action of Azo imidazole derivatives against COVID-19 main protease (M^pro): A computational study

Abhijit Chhetri¹, Sailesh Chettri², Pranesh Rai³, Biswajit Sinha³, Dhiraj Brahman²

Affiliations

¹ Department of Microbiology, St. Joseph's College, Darjeeling, 734104, India.
² Department of Chemistry, St. Joseph's College, Darjeeling, 734104, India.
³ Department of Chemistry, University of North Bengal, Darjeeling, 734013, India.

PMID: 32904625
PMCID: PMC7456803
DOI: 10.1016/j.molstruc.2020.129178

Exploration of inhibitory action of Azo imidazole derivatives against COVID-19 main protease (M^pro): A computational study

Abhijit Chhetri et al. J Mol Struct. 2021.

. 2021 Jan 15:1224:129178.

doi: 10.1016/j.molstruc.2020.129178. Epub 2020 Aug 31.

Authors

Abhijit Chhetri¹, Sailesh Chettri², Pranesh Rai³, Biswajit Sinha³, Dhiraj Brahman²

Affiliations

¹ Department of Microbiology, St. Joseph's College, Darjeeling, 734104, India.
² Department of Chemistry, St. Joseph's College, Darjeeling, 734104, India.
³ Department of Chemistry, University of North Bengal, Darjeeling, 734013, India.

PMID: 32904625
PMCID: PMC7456803
DOI: 10.1016/j.molstruc.2020.129178

Abstract

Four novel ionic liquid tagged azo-azomethine derivatives (L1-L4) have been prepared by the condensation reaction of azo-coupled ortho-vaniline precursor with amino functionalised imidazole derivative and the synthesized derivatives (L1-L4) have been characterized by different analytical and spectroscopic techniques. Molecular docking studies were carried out to ascertain the inhibitory action of studied ligands (L1-L4) against the Main Protease (6LU7) of novel coronavisrus (COVID-19). The result of the docking of L1-L4 showed a significant inhibitory action against the Main protease (M^pro) of SARS-CoV-2 and the binding energy (ΔG) values of the ligands (L1-L4) against the protein 6LU7 have found to be -7.7 Kcal/mole (L1), -7.0 Kcal/mole (L2), -7.9 Kcal/mole (L3), and -7.9 Kcal/mole (L4).The efficiency of the ligands has been compared with the FDA approved and clinically trial drugs such as remdesivir, Chloroquin and Hydroxychloroquin and native ligand N3 of main protease 6LU7 to ascertain the inhibitory potential of the studied ligands (L1-L4) against the protein 6LU7. Pharmacokinetic properties (ADME) of the ligands (L1-L4) have also been studied.

Keywords: Azo imidazole; Binding energy; Chloroquin; Hydroxychloroquin; Molecular docking; Pharmacokinetics; Remdesivir; SARS-CoV-2 Mpro.

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Conflict of interest statement

The authors do not have any conflict of interest.

Figures

Image, graphical abstract — **Graphical abstract**

Fig 1 — **Fig. 1**
Structure of Azo Imidazole ligands (L1-L4).

**Scheme 1**
Syntheses of Azo Imidazole derivatives L1-L4.

Fig 2 — **Fig. 2**
Infrared Spectra of Compound L1.

Fig 3 — **Fig. 3**
¹H NMR spectra of compound L1.

Fig 4 — **Fig. 4**
Structure of M^pro of SARS-Cov-2 with domain I, II and III (yellow circle represents catalytically active site).

Fig 5 — **Fig. 5**
Visualization of docking of Ligand L1 docked in M^pro (6LU7) (A) Best binding mode of protein (Ligand L1 as green and red stick), (B) Amino acid residues involved in hydrogen bonding interaction (green dash line represents H-bonding) and (C) Binding interaction (2D) of ligand L1 with amino acid residues of protein 6LU7 (green dash line represents H-bonding and yellow dashed line represents π-sulpher interaction).

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[1] MacIntyre C.R. Global spread of COVID-19 and pandemic potential. Global Biosecurity. 2020;1(3) doi: 10.31646/gbio.55. - DOI

[2] MacIntyre C.R. Global spread of COVID-19 and pandemic potential. Global Biosecurity. 2020;1(3) doi: 10.31646/gbio.55. - DOI

[3] Li W.H., Moore M.J., Vasilieva N., Sui J.H., Wong S.K., Berne M.A., Somasundaran M., Sullivan J.L., Luzuriaga K., Greenough T.C., Choe H., Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450–454. doi: 10.1038/nature02145. - DOI - PMC - PubMed

[4] Li W.H., Moore M.J., Vasilieva N., Sui J.H., Wong S.K., Berne M.A., Somasundaran M., Sullivan J.L., Luzuriaga K., Greenough T.C., Choe H., Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450–454. doi: 10.1038/nature02145. - DOI - PMC - PubMed

[5] Sun M.L., Yang J.M., Sun Y.P., Su G.H. Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia. Chin. J. Tuber. Resp. dis. 2020;43(3):219‐222. doi: 10.3760/cma.j.issn.1001-0939.2020.03.016. - DOI - PubMed

[6] Sun M.L., Yang J.M., Sun Y.P., Su G.H. Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia. Chin. J. Tuber. Resp. dis. 2020;43(3):219‐222. doi: 10.3760/cma.j.issn.1001-0939.2020.03.016. - DOI - PubMed

[7] Harismah K., Mirzaei M. Favipiravir: structural Analysis and Activity against COVID-19. Adv. J. Chem. Section B. 2020;2(2):55–60. doi: 10.33945/SAMI/AJCB.2020.2.3. - DOI

[8] Harismah K., Mirzaei M. Favipiravir: structural Analysis and Activity against COVID-19. Adv. J. Chem. Section B. 2020;2(2):55–60. doi: 10.33945/SAMI/AJCB.2020.2.3. - DOI

[9] 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 SARS-CoV-2 and discovery of its inhibitors. Nature. 2020:1–24. doi: 10.1038/s41586-020-2223-y. - DOI - PubMed

[10] 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 SARS-CoV-2 and discovery of its inhibitors. Nature. 2020:1–24. doi: 10.1038/s41586-020-2223-y. - DOI - PubMed

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Exploration of inhibitory action of Azo imidazole derivatives against COVID-19 main protease (M^pro): A computational study

Affiliations

Exploration of inhibitory action of Azo imidazole derivatives against COVID-19 main protease (M^pro): A computational study

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Affiliations

Abstract

Conflict of interest statement

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