European Journal of Chemistry

Quinoline analogue as a potential inhibitor of SARS-CoV-2 main protease: ADMET prediction, molecular docking and dynamics simulation analysis


Main Article Content

Praveen Kumar
Santhosha Sangapurada Mahantheshappa
Sakthivel Balasubramaniyan
Nayak Devappa Satyanarayan
Rajeshwara Achur


The novel coronavirus (COVID-19) has triggered a major human turmoil worldwide by posing challenges regarding infection prevention, disease diagnosis, and treatment. Several drugs including remdesivir (RDV), hydroxychloroquine (HCQ), and others are being used to treat COVID-19, although these are not specifically proven drugs. Thus, it is very critical to understand COVID-19 drug targets and their interactions with candidate drugs. Here, we attempted in silico screening of ten quinoline analogs (Q1-Q10) against the five main proteases of SARS-CoV-2 by docking and dynamics analysis. The prediction of the ADMET profile showed that the best docked quinolines are safe and possess drug-like properties. The molecular interaction and binding affinity of these small molecules were determined with respect to the five protease (Mpro) targets of SARS-CoV-2 (PDB ID: 6LU7, 6W63, 6M03, 6Y84 and 6YB7). The study indicated that the quinoline ligands Q4, Q5, Q6, Q7, Q8, Q9, and Q10as probable inhibitors against SARS-CoV-2 Mpro and showed favorable binding interaction with the amino acid Glu166 of 6Y84, 6LU7and 6M03. Furthermore, Q9 has a highly significant docking score and binding affinity with all fiveCOVID-19 receptors having a minimum of two H-bonds, which is remarkable compared to HCQ, RDV, and other quinolines. The dynamics simulation analysis of this potent drug candidate Q9 with 6LU7 indicated high stability of the complex. In conclusion, our findings indicate that all of these quinolines in general possess good binding affinity and Q9 can serve as a good quinoline scaffold for the design of new antiviral agents to target the active site of SARS-CoV-2 MPro.

icon graph This Abstract was viewed 523 times | icon graph Article PDF downloaded 186 times

How to Cite
Kumar, P.; Mahantheshappa, S. S.; Balasubramaniyan, S.; Satyanarayan, N. D.; Achur, R. Quinoline Analogue As a Potential Inhibitor of SARS-CoV-2 Main Protease: ADMET Prediction, Molecular Docking and Dynamics Simulation Analysis. Eur. J. Chem. 2023, 14, 30-38.

Article Details

Crossref - Scopus - Google - European PMC

[1]. Yang, P.; Ding, Y.; Xu, Z.; Pu, R.; Li, P.; Yan, J.; Liu, J.; Meng, F.; Huang, L.; Shi, L.; Jiang, T.; Qin, E.; Zhao, M.; Zhang, D.; Zhao, P.; Yu, L.; Wang, Z.; Hong, Z.; Xiao, Z.; Xi, Q.; Zhao, D.; Yu, P.; Zhu, C.; Chen, Z.; Zhang, S.; Ji, J.; Cao, G.; Wang, F. Epidemiological and Clinical Features of COVID-19 Patients with and without Pneumonia in Beijing, China. BioRxiv, 2020.

[2]. Weiner, D. L.; Balasubramaniam, V.; Shah, S. I.; Javier, J. R.; Pediatric Policy Council. COVID-19 Impact on Research, Lessons Learned from COVID-19 Research, Implications for Pediatric Research. Pediatr. Res. 2020, 88 (2), 148-150.

[3]. Smyth, T.; Ramachandran, V. N.; Smyth, W. F. A Study of the Antimicrobial Activity of Selected Naturally Occurring and Synthetic Coumarins. Int. J. Antimicrob. Agents 2009, 33 (5), 421-426.

[4]. Yazdany, J.; Kim, A. H. J. Use of Hydroxychloroquine and Chloroquine during the COVID-19 Pandemic: What Every Clinician Should Know. Ann. Intern. Med. 2020, 172 (11), 754-755.

[5]. Wang, M.; Cao, R.; Zhang, L.; Yang, X.; Liu, J.; Xu, M.; Shi, Z.; Hu, Z.; Zhong, W.; Xiao, G. Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-NCoV) in Vitro. Cell Res. 2020, 30 (3), 269-271.

[6]. Gao, J.; Tian, Z.; Yang, X. Breakthrough: Chloroquine Phosphate Has Shown Apparent Efficacy in Treatment of COVID-19 Associated Pneumonia in Clinical Studies. Biosci. Trends 2020, 14 (1), 72-73.

[7]. Li, G.; De Clercq, E. Therapeutic Options for the 2019 Novel Coronavirus (2019-NCoV). Nat. Rev. Drug Discov. 2020, 19 (3), 149-150.

[8]. Vijayalakshmi, P.; Daisy, P. Effective Interaction Studies for Inhibition of DNA Ligase Protein from Staphylococcus Aureus. J. Recept. Signal Transduct. Res. 2015, 35 (1), 15-25.

[9]. Choy, K.-T.; Wong, A. Y.-L.; Kaewpreedee, P.; Sia, S. F.; Chen, D.; Hui, K. P. Y.; Chu, D. K. W.; Chan, M. C. W.; Cheung, P. P.-H.; Huang, X.; Peiris, M.; Yen, H.-L. Remdesivir, Lopinavir, Emetine, and Homoharring tonine Inhibit SARS-CoV-2 Replication in Vitro. Antiviral Res. 2020, 178 (104786), 104786.

[10]. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; Niu, P.; Zhan, F.; Ma, X.; Wang, D.; Xu, W.; Wu, G.; Gao, G. F.; Tan, W.; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382 (8), 727-733.

[11]. Kwiek, J. J.; Haystead, T. A. J.; Rudolph, J. Kinetic Mechanism of Quinone Oxidoreductase 2 and Its Inhibition by the Antimalarial Quinolines. Biochemistry 2004, 43 (15), 4538-4547.

[12]. Devaux, C. A.; Rolain, J.-M.; Colson, P.; Raoult, D. New Insights on the Antiviral Effects of Chloroquine against Coronavirus: What to Expect for COVID-19? Int. J. Antimicrob. Agents 2020, 55 (5), 105938.

[13]. Tsiang, H.; Superti, F. Ammonium Chloride and Chloroquine Inhibit Rabies Virus Infection in Neuroblastoma Cells. Arch. Virol. 1984, 81 (3-4), 377-382.

[14]. Kronenberger, P.; Vrijsen, R.; Boeyé, A. Chloroquine Induces Empty Capsid Formation during Poliovirus Eclipse. J. Virol. 1991, 65 (12), 7008-7011.

[15]. Savarino, A.; Gennero, L.; Sperber, K.; Boelaert, J. R. The Anti-HIV-1 Activity of Chloroquine. J. Clin. Virol. 2001, 20 (3), 131-135.

[16]. Bishop, N. E. Examination of Potential Inhibitors of Hepatitis A Virus Uncoating. Intervirology 1998, 41 (6), 261-271.

[17]. Delvecchio, R.; Higa, L. M.; Pezzuto, P.; Valadão, A. L.; Garcez, P. P.; Monteiro, F. L.; Loiola, E. C.; Dias, A. A.; Silva, F. J. M.; Aliota, M. T.; Caine, E. A.; Osorio, J. E.; Bellio, M.; O'Connor, D. H.; Rehen, S.; de Aguiar, R. S.; Savarino, A.; Campanati, L.; Tanuri, A. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models. Viruses 2016, 8 (12), 322.

[18]. Dowall, S. D.; Bosworth, A.; Watson, R.; Bewley, K.; Taylor, I.; Rayner, E.; Hunter, L.; Pearson, G.; Easterbrook, L.; Pitman, J.; Hewson, R.; Carroll, M. W. Chloroquine Inhibited Ebola Virus Replication in Vitro but Failed to Protect against Infection and Disease in the in Vivo Guinea Pig Model. J. Gen. Virol. 2015, 96 (12), 3484-3492.

[19]. Savarino, A.; Boelaert, J. R.; Cassone, A.; Majori, G.; Cauda, R. Effects of Chloroquine on Viral Infections: An Old Drug against Today's Diseases? Lancet Infect. Dis. 2003, 3 (11), 722-727.

[20]. Keyaerts, E.; Li, S.; Vijgen, L.; Rysman, E.; Verbeeck, J.; Van Ranst, M.; Maes, P. Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice. Antimicrob. Agents Chemother. 2009, 53 (8), 3416-3421.

[21]. Cortegiani, A.; Ingoglia, G.; Ippolito, M.; Giarratano, A.; Einav, S. A Systematic Review on the Efficacy and Safety of Chloroquine for the Treatment of COVID-19. J. Crit. Care 2020, 57, 279-283.

[22]. Fadelelmoula, T. Efficacy and Safety of Hydroxychloroquine in Treating COVID-19 Pneumonia: Uncertainty of Data and Changing Treatment Protocols. J. Lung Pulm. Respir. Res. 2020, 7 (2), 62-65.

[23]. Wu, T.; Li, Y.; Liu, G.; Li, J.; Wang, L.; Du, L.; Chinese Clinical Registry. Chinese Clinical Trial Registry: Mission, Responsibility and Operation: Chinese Clinical Trial Registry: Mission, Responsibility and Operation. J. Evid. Based Med. 2011, 4 (3), 165-167.

[24]. Liu, J.; Cao, R.; Xu, M.; Wang, X.; Zhang, H.; Hu, H.; Li, Y.; Hu, Z.; Zhong, W.; Wang, M. Hydroxychloroquine, a Less Toxic Derivative of Chloroquine, Is Effective in Inhibiting SARS-CoV-2 Infection in Vitro. Cell Discov. 2020, 6 (1), 16.

[25]. Khuroo, M. S. Chloroquine and hydroxychloroquine in coronavirus disease 2019 (COVID-19). Facts, fiction and the hype: a critical appraisal. Int. J. Antimicrob. Agents 2020, 56, 106101.

[26]. Rodriguez-Valero, N.; Vera, I.; Torralvo, M. R.; De Alba, T.; Ferrer, E.; Camprubi, D.; AlmuedoRiera, A.; Gallego, R. S.; Muelas, M.; Pinazo, M. J.; Muñoz, J. Malaria Prophylaxis Approach during COVID-19 Pandemic. Travel Med. Infect. Dis. 2020, 38 (101716), 101716.

[27]. Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B. 2020, 10, 766-788.

[28]. Kumar, P.; Uthaiah, C. A.; Mahantheshappa, S. S.; Satyanarayan, N. D.; Madhunapantula, S. V.; Kumar, H. S. S.; Achur, R. Antiproliferative Potential, Quantitative Structure-Activity Relationship, Cheminfor matic and Molecular Docking Analysis of Quinoline and Benzofuran Derivatives. Eur. J. Chem. 2020, 11 (3), 223-234.

[29]. Mahantheshappa, S. S.; Shivanna, H.; Satyanarayan, N. D. Synthesis, Antimicrobial, Antioxidant, and ADMET Studies of Quinoline Derivatives. Eur. J. Chem. 2021, 12 (1), 37-44.

[30]. ChemAxon - Software Solutions and Services for Chemistry & Biology, Marvin Sketch.17.21.0 (accessed Jul 15, 2021).

[31]. Wishart, D. S.; Feunang, Y. D.; Guo, A. C.; Lo, E. J.; Marcu, A.; Grant, J. R.; Sajed, T.; Johnson, D.; Li, C.; Sayeeda, Z.; Assempour, N.; Iynkkaran, I.; Liu, Y.; Maciejewski, A.; Gale, N.; Wilson, A.; Chin, L.; Cummings, R.; Le, D.; Pon, A.; Knox, C.; Wilson, M. DrugBank 5.0: A Major Update to the DrugBank Database for 2018. Nucleic Acids Res. 2018, 46 (D1), D1074-D1082.

[32]. Schüttelkopf, A. W.; van Aalten, D. M. F. PRODRG: A Tool for High-Throughput Crystallography of Protein-Ligand Complexes. Acta Crystallogr. D Biol. Crystallogr. 2004, 60 (Pt 8), 1355-1363.

[33]. Sastry, G. M.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments. J. Comput. Aided Mol. Des. 2013, 27 (3), 221-234.

[34]. 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, 582 (7811), 289-293.

[35]. Estrada, E. Topological Analysis of SARS CoV-2 Main Protease. Chaos 2020, 30 (6), 061102.

[36]. Zhang, B.; Zhao, Y.; Jin, Z.; Liu, X.; Yang, H.; Rao, Z. The Crystal Structure of COVID-19 Main Protease in Apo Form. Worldwide Protein Data Bank March 11, 2020.

[37]. Douangamath, A.; Fearon, D.; Gehrtz, P.; Krojer, T.; Lukacik, P.; Owen, C. D.; Resnick, E.; Strain-Damerell, C.; Aimon, A.; Ábrányi-Balogh, P.; Brandão-Neto, J.; Carbery, A.; Davison, G.; Dias, A.; Downes, T. D.; Dunnett, L.; Fairhead, M.; Firth, J. D.; Jones, S. P.; Keeley, A.; Keserü, G. M.; Klein, H. F.; Martin, M. P.; Noble, M. E. M.; O'Brien, P.; Powell, A.; Reddi, R. N.; Skyner, R.; Snee, M.; Waring, M. J.; Wild, C.; London, N.; von Delft, F.; Walsh, M. A. Crystallographic and Electrophilic Fragment Screening of the SARS-CoV-2 Main Protease. Nat. Commun. 2020, 11 (1), 5047.

[38]. Owen, C. D.; Lukacik, P.; Strain-Damerell, C. M.; Douangamath, A.; Powell, A. J.; Fearon, D.; Brandao-Neto, J.; Crawshaw, A. D.; Aragao, D.; Williams, M.; Flaig, R.; Hall, D. R.; McAuley, K. E.; Mazzorana, M.; Stuart, D. I.; von Delft, F.; Walsh, M. A. SARS-CoV-2 Main Protease with Unliganded Active Site (2019-NCoV, Coronavirus Disease 2019, COVID-19). Worldwide Protein Data Bank March 11, 2020.

[39]. Pandey, A. K.; Siddiqui, M. H.; Dutta, R. Drug-Likeness Prediction of Designed Analogues of Isoniazid Standard Targeting FabI Enzyme Regulation from P. Falciparum. Bioinformation 2019, 15 (5), 364-368.

[40]. Thakur, Z.; Dharra, R.; Saini, V.; Kumar, A.; Mehta, P. K. Insights from the Protein-Protein Interaction Network Analysis of Mycobacterium Tuberculosis Toxin-Antitoxin Systems. Bioinformation 2017, 13 (11), 380-387.

[41]. Goddard, T. D.; Huang, C. C.; Ferrin, T. E. Visualizing Density Maps with UCSF Chimera. J. Struct. Biol. 2007, 157 (1), 281-287.

[42]. Norgan, A. P.; Coffman, P. K.; Kocher, J.-P. A.; Katzmann, D. J.; Sosa, C. P. Multilevel Parallelization of AutoDock 4.2. J. Cheminform. 2011, 3 (1), 12.

[43]. Ray, S.; Madrid, P. B.; Catz, P.; LeValley, S. E.; Furniss, M. J.; Rausch, L. L.; Guy, R. K.; DeRisi, J. L.; Iyer, L. V.; Green, C. E.; Mirsalis, J. C. Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models. J. Med. Chem. 2010, 53 (9), 3685-3695.

[44]. Balasubramaniyan, S.; Irfan, N.; Umamaheswari, A.; Puratchikody, A. Design and Virtual Screening of Novel Fluoroquinolone Analogs as Effective Mutant DNA GyrA Inhibitors against Urinary Tract Infection-Causing Fluoroquinolone Resistant Escherichia Coli. RSC Adv. 2018, 8 (42), 23629-23647.

[45]. Kumar, P.; Satyanarayan, N. D.; Madhunapantula, S. R. V.; Kumar, H. S. S.; Achur, R. In Silico Screening for the Interaction of Small Molecules with Their Targets and Evaluation of Therapeutic Efficacy by Free Online Tools. Eur. J. Chem. 2020, 11 (2), 168-178.

[46]. Han, Y.; Zhang, J.; Hu, C. Q.; Zhang, X.; Ma, B.; Zhang, P. In Silico ADME and Toxicity Prediction of Ceftazidime and Its Impurities. Front. Pharmacol. 2019, 10, 434.

[47]. Small-Molecule Drug Discovery Suite 2013 QikProp, Version 3.8, Schrödinger, LLC, New York, NY, 2013.

[48]. Clark, D. E. Rapid Calculation of Polar Molecular Surface Area and Its Application to the Prediction of Transport Phenomena. 1. Prediction of Intestinal Absorption. J. Pharm. Sci. 1999, 88 (8), 807-814.

[49]. O'Hagan, S.; Kell, D. B. The Apparent Permeabilities of Caco-2 Cells to Marketed Drugs: Magnitude, and Independence from Both Biophysical Properties and Endogenite Similarities. PeerJ 2015, 3 (e1405), e1405.

[50]. Yang, H.; Xie, W.; Xue, X.; Yang, K.; Ma, J.; Liang, W.; Zhao, Q.; Zhou, Z.; Pei, D.; Ziebuhr, J.; Hilgenfeld, R.; Yuen, K. Y.; Wong, L.; Gao, G.; Chen, S.; Chen, Z.; Ma, D.; Bartlam, M.; Rao, Z. Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases. PLoS Biol. 2005, 3 (10), e324.

[51]. Thakkar, S. S.; Shelat, F.; Thakor, P. Magical bullets from an indigenous Indian medicinal plant Tinosporacordifolia: An in silico approach for the antidote of SARS-CoV-2. Egyptian J. Petroleum 2021, 30(1), 53-66.

[52]. Hatada, R.; Okuwaki, K.; Mochizuki, Y.; Handa, Y.; Fukuzawa, K.; Komeiji, Y.; Okiyama, Y.; Tanaka, S. Fragment Molecular Orbital Based Interaction Analyses on COVID-19 Main Protease - Inhibitor N3 Complex (PDB ID: 6LU7). J. Chem. Inf. Model. 2020, 60 (7), 3593-3602.

[53]. Alexpandi, R.; De Mesquita, J. F.; Pandian, S. K.; Ravi, A. V. Quinolines-Based SARS-CoV-2 3CLpro and RdRp Inhibitors and Spike-RBD-ACE2 Inhibitor for Drug-Repurposing against COVID-19: An in Silico Analysis. Front. Microbiol. 2020, 11, 1796.

[54]. Zumla, A.; Chan, J. F. W.; Azhar, E. I.; Hui, D. S. C.; Yuen, K.-Y. Coronaviruses - Drug Discovery and Therapeutic Options. Nat. Rev. Drug Discov. 2016, 15 (5), 327-347.

[55]. Zhang, W.; Zhao, Y.; Zhang, F.; Wang, Q.; Li, T.; Liu, Z.; Wang, J.; Qin, Y.; Zhang, X.; Yan, X.; Zeng, X.; Zhang, S. The Use of Anti-Inflammatory Drugs in the Treatment of People with Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists from China. Clin. Immunol. 2020, 214 (108393), 108393.

[56]. Fantini, J.; Chahinian, H.; Yahi, N. Synergistic Antiviral Effect of Hydroxychloroquine and Azithromycin in Combination against SARS-CoV-2: What Molecular Dynamics Studies of Virus-Host Interactions Reveal. Int. J. Antimicrob. Agents 2020, 56 (2), 106020.

[57]. Schilling, W. H.; White, N. J. Does Hydroxychloroquine Still Have Any Role in the COVID-19 Pandemic? Expert Opin. Pharmacother. 2021, 22 (10), 1257-1266.

[58]. Elfiky, A. A. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp): A Molecular Docking Study. Life Sci. 2020, 253 (117592), 117592.

[59]. Majumder, R.; Mandal, M. Screening of plant-based natural compounds as a potential COVID-19 main protease inhibitor: An in silico docking and molecular dynamics simulation approach. J. Biomol. Struct. Dyn. 2022, 40, 696-711.

[60]. Kajal, K.; Panda, A. K.; Bhat, J.; Chakraborty, D.; Bose, S.; Bhattacharjee, P.; Sarkar, T.; Chatterjee, S.; Kar, S. K.; Sa, G. Andrographolide Binds to ATP-Binding Pocket of VEGFR2 to Impede VEGFA-Mediated Tumor-Angiogenesis. Sci. Rep. 2019, 9 (1), 4073.

[61]. Al-Jaidi, B. A.; Telfah, S. T.; Bardaweel, S. K.; Deb, P. K.; Borah, P.; Venugopala, K. N.; Bataineh, Y. A.; Al Khames Aga, Q. A. Anticancer Activity and in Silico ADMET Properties of 2,4,5-Trisubstituted thiazole Derivatives. Curr. Drug Metab. 2020, 21.

Supporting Agencies

Most read articles by the same author(s)

Most read articles by the same author(s)


Dimensions - Altmetric - scite_ - PlumX

Downloads and views


Download data is not yet available.


Metrics Loading ...
License Terms

License Terms


Copyright © 2024 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License ( By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution, or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License ( are administered by Atlanta Publishing House LLC (European Journal of Chemistry).