Molecular docking analysis of rutin reveals possible inhibition of SARS-CoV-2 vital proteins

10.1016/j.jtcme.2021.01.006

Fazlur Rahman；Shams Tabrez；Rahat Ali；Ali S. Alqahtani；Mohammad Z. Ahmed；Abdur Rub

Pandemic ； Drug-targets ； Flavonoids ； M^(pro) ； RdRp ； ADMET

Journal of Traditional and Complementary Medicine

11卷2期（2021 / 03 / 01）

173 - 179

英文

Background and aim: COVID-19 emerged by the end of 2019 in Wuhan, China. It spreaded and became a public health emergency all over the world by mid of April 2020. Flavonoids are specialized metabolites that have antimicrobial properties including anti-viral activity. Rutin, a medicinally important flavonoid belongs to one of the best natural antioxidant classes. It has antiprotozoal, antibacterial, and antiviral properties. Keeping the antimicrobial potential of rutin in mind, we studied its role in the inhibition of essential proteins of SARS-CoV-2 including main protease (M^(pro)), RNA-dependent RNA polymerase (RdRp), papain-like protease (PL^(pro)), and spike (S)-protein through different in silico approaches. Experimental procedure: Molecular docking, inhibition constant, hydrogen bond calculations, and ADMET-properties prediction were performed using different softwares. Results and conclusion: Molecular docking study showed significant binding of rutin with M^(pro), RdRp, PL^(pro), and S-proteins of SARS-CoV-2. Out of these four proteins, M^(pro) exhibited the strongest binding affinity with the least binding energy (-8.9 kcal/mol) and stabilized through hydrogen bonds with bond lengths ranging from 1.18 Å to 3.17 Å as well as hydrophobic interactions. The predicted ADMET and bioactivity showed its optimal solubility, non-toxic, and non-carcinogenic properties. The values of the predicted inhibitory constant of the rutin with SARS-CoV-2 vital proteins ranged between 5.66 μM and 6.54 μM which suggested its promising drug candidature. This study suggested rutin alone or in combination as a dietary supplement may be used to fight against COVID-19 after detailed in vitro and in vivo studies.

1. Arya, R,Das, A,Prashar, V,Kumar, M(2020).,未出版
2. Báez-Santos, YM,St John, SE,Mesecar, AD(2015).The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.Antivir Res,115,21-38.
3. Barretto, N,Jukneliene, D,Ratia, K,Chen, Z,Mesecar, AD,Baker, SC(2005).The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquiti-nating activity.J Virol,79(24),15189-15198.
4. Belouzard, S,Millet, JK,Licitra, BN,Whittaker, GR(2012).Mechanisms of coronavirus cell entry mediated by the viral spike protein.Viruses,4(6),1011-1033.
5. Ben-Shabat, S,Yarmolinsky, L,Porat, D,Dahan, A(2020).Antiviral effect of phyto-chemicals from medicinal plants: applications and drug delivery strategies.Drug delivery and translational research,10(2),354-367.
6. Bosch, BJ,Martina, BE,Van Der Zee, R(2004).Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides.Proc Natl Acad Sci Unit States Am,101(22),8455-8460.
7. Chen, D,Oezguen, N,Urvil, P,Ferguson, C,Dann, SM,Savidge, TC(2016).Regulation of protein-ligand binding affinity by hydrogen bond pairing.Science advances,2(3),e1501240.
8. Cheron, N,Yu, C,Kolawole, AO,Shakhnovich, EI,Wobus, CE(2015).Repurposing of rutin for the inhibition of norovirus replication.Arch Virol,160(9),2353-2358.
9. Choi, JH,Kim, DW,Park, SE(2015).Anti-thrombotic effect of rutin isolated from Dendropanax morbifera Leveille.J Biosci Bioeng,120(2),181-186.
10. Dallakyan, S,Olson, AJ(2015).Small-molecule library screening by docking with PyRx.Methods Mol Biol,1263,243-250.
11. de Groot, RJ,Luytjes, W,Horzinek, MC,van der Zeijst, BA,Spaan, WJ,Lenstra, JA(1987).Evidence for a coiled-coil structure in the spike proteins of coronaviruses.J Mol Biol,196(4),963-966.
12. Du, X,Li, Y,Xia, YL(2016).Insights into protein-ligand interactions: mechanisms, models, and methods.Int J Mol Sci.,17(2),144-178.
13. Eckert, DM,Kim, PS(2001).Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region.Proc. Natl. Acad. Sci. U.S.A.,98(20),11187-11192.
14. Gallagher, TM,Buchmeier, MJ(2001).Coronavirus spike proteins in viral entry and pathogenesis.Virology,279(2),371-374.
15. Ganeshpurkar, A,Saluja, AK(2017).The pharmacological potential of rutin.Saudi Pharmaceut J: SPJ: the official publication of the Saudi Pharmaceutical Society,25(2),149-164.
16. Gao, Y,Yan, L,Huang, Y(2020).Structure of the RNA-dependent RNA polymerase from COVID-19 virus.Science,368(6492),779-782.
17. Hegyi, A,Ziebuhr, J(2002).Conservation of substrate specificities among coronavirus main proteases.J Gen Virol,83(Pt 3),595-599.
18. Hu, D,Zhu, C,Ai, L(2018).Genomic characterization and infectivity of a novel SARS-like coronavirus in Chinese bats.Emerg Microb Infect,7(1),154.
19. Huang, J,Song, W,Huang, H,Sun, Q(2020).Pharmacological therapeutics targeting RNA-dependent RNA polymerase, proteinase and spike protein: from mechanistic studies to clinical trials for COVID-19.J Clin Med,9(4),1131.
20. Huang, WY,Zhang, HC,Liu, WX,Li, CY(2012).Survey of antioxidant capacity and phenolic composition of blueberry, blackberry, and strawberry in Nanjing.J Zhejiang Univ - Sci B.,13(2),94-102.
21. Hughes, JP,Rees, S,Kalindjian, SB,Philpott, KL(2011).Principles of early drug discovery.Br J Pharmacol,162(6),1239-1249.
22. Jin, Z,Du, X,Xu, Y(2020).Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors.Nature,582(7811),289-293.
23. Jo, S,Kim, S,Shin, DH,Kim, MS(2020).Inhibition of SARS-CoV 3CL protease by flavonoids.J Enzym Inhib Med Chem,35(1),145-151.
24. Kashif, M,Hira, SK,Upadhyaya, A(2019).In silico studies and evaluation of antiparasitic role of a novel pyruvate phosphate dikinase inhibitor in Leish-mania donovani infected macrophages.Int J Antimicrob Agents,53(4),508-514.
25. Kashif, M,Tabrez, S,Husein, A(2018).Identification of novel inhibitors against UDP-galactopyranose mutase to combat leishmaniasis.J Cell Biochem,119(3),2653-2665.
26. Lan, J,Ge, J,Yu, J(2020).Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature,581(7807),215-220.
27. Li, W,Moore, MJ,Vasilieva, N(2003).Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature,426(6965),450-454.
28. Lin, YJ,Chang, YC,Hsiao, NW(2012).Fisetin and rutin as 3C protease inhibitors of enterovirus A71.J Virol Methods,182(1-2),93-98.
29. Lu, H,Stratton, CW,Tang, YW(2020).Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle.J Med Virol,92(4),401-402.
30. Mohammadi, N,Shaghaghi, N(2020).,未出版
31. Mokhnache, K,Madoui, S,Khither, H,Charef, N(2019).Drug-likeness and pharmaco-kinetics of a bis-phenolic ligand: evaluations by computational methods.Scholars J Appl Med Sci,1,167-173.
32. O’Boyle, NM,Banck, M,James, CA(2011).An open chemical toolbox.J Cheminf,3,33.
33. Patel, K,Patel, DK(2019).The Beneficial Role of Rutin, a Naturally Occurring Flavonoid in Health Promotion and Disease Prevention: A Systematic Review and Update.Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases
34. Pillaiyar, T,Manickam, M,Namasivayam, V,Hayashi, Y,Jung, S-H(2016).An overview of severe acute respiratory syndromeecoronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy.J Med Chem,59(14),6595-6628.
35. Posthuma, CC,Te Velthuis, AJW,Snijder, EJ(2017).Nidovirus RNA polymerases: complex enzymes handling exceptional RNA genomes.Virus Res,234,58-73.
36. Raj, S,Sasidharan, S,Dubey, VK,Saudagar, P(2019).Identification of lead molecules against potential drug target protein MAPK4 from L. donovani: an in-silico approach using docking, molecular dynamics and binding free energy calculation.PloS One,14(8),e0221331.
37. Rappé, AK,Casewit, CJ,Colwell, K,Goddard, III, WA,Skiff, WM(1992).UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations.JJotAcs,114(25),10024-10035.
38. Snijder, EJ,Decroly, E,Ziebuhr, J(2016).The nonstructural proteins directing corona-virus RNA synthesis and processing.Adv Virus Res,96,59-126.
39. Tabrez, S,Rahman, F,Ali, R(2021).Cynaroside inhibits Leishmania donovani UDP-galactopyranose mutase and induces reactive oxygen species to exert anti-leishmanial response.Biosci Rep,21(1),1-14.
40. Trott, O,Olson, AJ(2010).AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J Comput Chem,31(2),455-461.
41. Ungell, A-L(1997).In vitro absorption studies and their relevance to absorption from the GI tract.Drug Dev Ind Pharm,23(9),879-892.
42. Wadood, A,Ahmed, N,Shah, L,Ahmad, A,Hassan, H,Shams, S(2013).In-silico drug design: an approach which revolutionarised the drug discovery process.OA drug design & delivery,1(1),3.
43. Wang, C,Wang, P,Chen, X,Wang, W,Jin, Y(2015).Saururus chinensis (Lour.) Baill blocks enterovirus 71 infection by hijacking MEK1-ERK signaling pathway.Antivir Res,119,47-56.
44. Wu, F,Zhao, S,Yu, B(2020).A new coronavirus associated with human respiratory disease in China.Nature,579(7798),265-269.
45. Yang, Y,Islam, MS,Wang, J,Li, Y,Chen, X(2020).Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective.Int J Biol Sci,16(10),1708-1717.
46. Yao, C,Xi, C,Hu, K(2018).Inhibition of enterovirus 71 replication and viral 3C protease by quercetin.Virol J,15(1),116.
47. Yonekura-Sakakibara, K,Higashi, Y,Nakabayashi, R(2019).The origin and evolution of plant flavonoid metabolism.Front Plant Sci,10,943.
48. Zhang, L,Lin, D,Sun, X(2020).Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors.Science,368(6489),409-412.
49. Zhou, P,Yang, XL,Wang, XG(2020).A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature,579(7798),270-273.

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