Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

In silico Identification of Novel SARS-CoV-2 Main Protease and Nonstructural Protein 13 (nsp13) Inhibitors through Consensus Docking and Free Binding Energy Calculations

Author(s): Emilio Mateev*, Maya Georgieva and Alexander Zlatkov

Volume 26, Issue 6, 2023

Published on: 09 September, 2022

Page: [1242 - 1250] Pages: 9

DOI: 10.2174/1386207325666220818141112

Price: $65

Abstract

Background: A new strain of a novel disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been recently declared a pandemic by the World Health Organization (WHO). The virus results in significant mortality and morbidity across the planet; therefore, novel treatments are urgently required. Recently deposited crystallographic structures of SARS-CoV-2 proteins have ignited the interest in virtual screenings of large databases.

Objective: In the current study, we evaluated the inhibitory capacity of the IMPPAT phytochemical database (8500 compounds) and the SuperDRUG2 dataset (4000 compounds) in SARS-CoV-2 main protease and helicase Nsp13 through consensus-based docking simulations.

Methods: Glide and GOLD 5.3 were implemented in the in silico process. Further MM/GBSA calculations of the top 10 inhibitors in each protein were carried out to investigate the binding free energy of the complexes. An analysis of the major ligand-protein interactions was also conducted.

Results: After the docking simulations, we acquired 10 prominent phytochemicals and 10 FDAapproved drugs capable of inhibiting Nsp5 and Nsp13. Delphinidin 3,5,3'-triglucoside and hirsutidin 3-O-(6-O-p-coumaroyl)glucoside demonstrated the most favorable binding free energies against Nsp5 and Nsp13, respectively.

Conclusion: In conclusion, the analysis of the results identified that the phytochemicals demonstrated enhanced binding capacities compared to the FDA-approved database.

Keywords: SARS-CoV-2, main protease, Nsp13, consensus docking, virtual screening, molecular docking.

« Previous
Graphical Abstract

[1]
Akshata, S.; Sneha, S.; Kimaya, K. Causes of deaths in COVID-19 patients. Int. J. Res. Pharm., 2020, 11(SPL1), 416-419.
[2]
Alamri, M.A.; Altharawi, A.; Alabbas, A.B.; Alossaimi, M.A.; Alqahtani, S.M. Structure-based virtual screening and molecular dynamics of phytochemicals derived from Saudi medicinal plants to identify potential COVID-19 therapeutics. Arab. J. Chem., 2020, 13(9), 7224-7234.
[http://dx.doi.org/10.1016/j.arabjc.2020.08.004] [PMID: 34909058]
[3]
Cao, X. COVID-19: Immunopathology and its implications for therapy. Nat. Rev. Immunol., 2020, 20(5), 269-270.
[http://dx.doi.org/10.1038/s41577-020-0308-3] [PMID: 32273594]
[4]
Elmezayen, A.D.; Al-Obaidi, A.; Şahin, A.T.; Yelekçi, K. Drug repurposing for coronavirus (COVID-19): In silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes. J. Biomol. Struct. Dyn., 2021, 39(8), 2980-2992.
[http://dx.doi.org/10.1080/07391102.2020.1758791] [PMID: 32306862]
[5]
Friesner, R.A.; Murphy, R.B.; Repasky, M.P.; Frye, L.L.; Greenwood, J.R.; Halgren, T.A.; Sanschagrin, P.C.; Mainz, D.T. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 2006, 49(21), 6177-6196.
[http://dx.doi.org/10.1021/jm051256o] [PMID: 17034125]
[6]
Gimeno, A.; Mestres-Truyol, J.; Ojeda-Montes, M.J.; Macip, G.; Saldivar-Espinoza, B.; Cereto-Massagué, A.; Pujadas, G.; Garcia-Vallvé, S. Prediction of novel inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through consensus docking and drug reposition. Int. J. Mol. Sci., 2020, 21(11), 3793.
[http://dx.doi.org/10.3390/ijms21113793] [PMID: 32471205]
[7]
Gurung, A.B. In silico structure modelling of SARS-CoV-2 Nsp13 helicase and Nsp14 and repurposing of FDA approved antiviral drugs as dual inhibitors. Gene Rep., 2020, 21, 100860-100860.
[http://dx.doi.org/10.1016/j.genrep.2020.100860] [PMID: 32875166]
[8]
Gurung, A.B.; Ali, M.A.; Lee, J.; Farah, M.A.; Al-Anazi, K.M. An updated review of computer-aided drug design and its application to COVID-19. BioMed Res. Int., 2021, 2021, 8853056-8853056.
[http://dx.doi.org/10.1155/2021/8853056] [PMID: 34258282]
[9]
Gyebi, G.A.; Ogunro, O.B.; Adegunloye, A.P.; Ogunyemi, O.M.; Afolabi, S.O. Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): An in silico screening of alkaloids and terpenoids from African medicinal plants. J. Biomol. Struct. Dyn., 2021, 39(9), 3396-3408.
[PMID: 32367767]
[10]
Houston, D.R.; Walkinshaw, M.D. Consensus docking: Improving the reliability of docking in a virtual screening context. J. Chem. Inf. Model., 2013, 53(2), 384-390.
[http://dx.doi.org/10.1021/ci300399w] [PMID: 23351099]
[11]
Islam, R.; Parves, M.R.; Paul, A.S.; Uddin, N.; Rahman, M.S.; Mamun, A.A.; Hossain, M.N.; Ali, M.A.; Halim, M.A. A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2. J. Biomol. Struct. Dyn., 2021, 39(9), 3213-3224.
[PMID: 32340562]
[12]
Krishna, S.; Augustin, Y.; Wang, J.; Xu, C.; Staines, H.M.; Platteeuw, H.; Kamarulzaman, A.; Sall, A.; Kremsner, P. Repurposing antimalarials to tackle the COVID-19 Pandemic. Trends Parasitol., 2021, 37(4), 357-357.
[http://dx.doi.org/10.1016/j.pt.2020.12.009] [PMID: 33541791]
[13]
Lyne, P.D.; Lamb, M.L.; Saeh, J.C. Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J. Med. Chem., 2006, 49(16), 4805-4808.
[http://dx.doi.org/10.1021/jm060522a] [PMID: 16884290]
[14]
Mahmud, S.; Mita, M.A.; Biswas, S.; Paul, G.K.; Promi, M.M.; Afrose, S.; Hasan, R.; Shimu, S.S.; Zaman, S.; Uddin, S.; Tallei, T.E.; Emran, T.B.; Saleh, A. Molecular docking and dynamics study to explore phytochemical ligand molecules against the main protease of SARS-CoV-2 from extensive phytochemical datasets. Expert Rev. Clin. Pharmacol., 2021, 14(10), 1305-1315.
[http://dx.doi.org/10.1080/17512433.2021.1959318] [PMID: 34301158]
[15]
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(2), 696-711.
[http://dx.doi.org/10.1080/07391102.2020.1817787] [PMID: 32897138]
[16]
Mohanraj, K.; Karthikeyan, B.S.; Vivek-Ananth, R.P.; Chand, R.P.B.; Aparna, S.R.; Mangalapandi, P.; Samal, A. IMPPAT: A curated database of Indian medicinal plants, phytochemistry and therapeutics. Sci. Rep., 2018, 8(1), 4329-4329.
[http://dx.doi.org/10.1038/s41598-018-22631-z] [PMID: 29531263]
[17]
Naik, V.R.; Munikumar, M.; Ramakrishna, U.; Srujana, M.; Goudar, G.; Naresh, P.; Kumar, B.N.; Hemalatha, R. Remdesivir (GS-5734) as a therapeutic option of 2019-nCOV main protease - in silico approach. J. Biomol. Struct. Dyn., 2021, 39(13), 4701-4714.
[http://dx.doi.org/10.1080/07391102.2020.1781694] [PMID: 32568620]
[18]
Newman, J.A.; Douangamath, A.; Yadzani, S.; Yosaatmadja, Y.; Aimon, A.; Brandão-Neto, J.; Dunnett, L.; Gorrie-Stone, T.; Skyner, R.; Fearon, D.; Schapira, M.; von Delft, F.; Gileadi, O. Structure, mechanism and crystallographic fragment screening of the SARS-CoV-2 NSP13 helicase. Nat. Commun., 2021, 12(1), 4848.
[http://dx.doi.org/10.1038/s41467-021-25166-6] [PMID: 34381037]
[19]
Palacio-Rodríguez, K.; Lans, I.; Cavasotto, C.N.; Cossio, P. Exponential consensus ranking improves the outcome in docking and receptor ensemble docking. Sci. Rep., 2019, 9(1), 5142-5142.
[http://dx.doi.org/10.1038/s41598-019-41594-3] [PMID: 30914702]
[20]
Pham, H.N.T.; Vuong, Q.V.; Bowyer, M.C.; Scarlett, C.J. Phytochemicals derived from catharanthus roseus and their health benefits. Technol, 2020, 8(4), 80.
[http://dx.doi.org/10.3390/technologies8040080]
[21]
Poli, G.; Martinelli, A.; Tuccinardi, T. Reliability analysis and optimization of the consensus docking approach for the development of virtual screening studies. J. Enzyme Inhib. Med. Chem., 2016, 31, 167-173.
[http://dx.doi.org/10.1080/14756366.2016.1193736]
[22]
Rohaim, M.A.; El Naggar, R.F.; Clayton, E.; Munir, M. Structural and functional insights into non-structural proteins of coronaviruses. Microb. Pathog., 2021, 150, 104641-104641.
[http://dx.doi.org/10.1016/j.micpath.2020.104641] [PMID: 33242646]
[23]
Rutwick Surya, U.; Praveen, N. A molecular docking study of SARS-CoV-2 main protease against phytochemicals of Boerhavia diffusa Linn. for novel COVID-19 drug discovery. Virusdisease, 2021, 32(1), 46-54.
[http://dx.doi.org/10.1007/s13337-021-00683-6] [PMID: 33758772]
[24]
Santamarina, A.B.; Pisani, L.P.; Baker, E.J.; Marat, A.D.; Valenzuela, C.A.; Miles, E.A.; Calder, P.C. Anti-inflammatory effects of oleic acid and the anthocyanin keracyanin alone and in combination: Effects on monocyte and macrophage responses and the NF-κB pathway. Food Funct., 2021, 12(17), 7909-7922.
[http://dx.doi.org/10.1039/D1FO01304A] [PMID: 34250536]
[25]
Singh, T.U.; Parida, S.; Lingaraju, M.C.; Kesavan, M.; Kumar, D.; Singh, R.K. Drug repurposing approach to fight COVID-19. Pharmacol. Rep., 2020, 72(6), 1479-1508.
[http://dx.doi.org/10.1007/s43440-020-00155-6] [PMID: 32889701]
[26]
Siramshetty, V.B.; Eckert, O.A.; Gohlke, B-O.; Goede, A.; Chen, Q.; Devarakonda, P.; Preissner, S.; Preissner, R. SuperDRUG2: A one stop resource for approved/marketed drugs. Nucleic Acids Res., 2018, 46(D1), D1137-D1143.
[http://dx.doi.org/10.1093/nar/gkx1088] [PMID: 29140469]
[27]
Vivek-Ananth, R.P.; Krishnaswamy, S.; Samal, A. Potential phytochemical inhibitors of SARS-CoV-2 helicase Nsp13: A molecular docking and dynamic simulation study. Mol. Divers., 2021, 1-14.
[PMID: 34117992]
[28]
Vukics, V.; Kery, A.; Bonn, G.K.; Guttman, A. Major flavonoid components of heartsease (Viola tricolor L.) and their antioxidant activities. Anal. Bioanal. Chem., 2008, 390(7), 1917-1925.
[http://dx.doi.org/10.1007/s00216-008-1885-3] [PMID: 18259733]
[29]
Yuce, M.; Cicek, E.; Inan, T.; Dag, A.B.; Kurkcuoglu, O.; Sungur, F.A. Repurposing of FDA-approved drugs against active site and potential allosteric drug-binding sites of COVID-19 main protease. Proteins, 2021, 89(11), 1425-1441.
[http://dx.doi.org/10.1002/prot.26164] [PMID: 34169568]
[30]
Zev, S.; Raz, K.; Schwartz, R.; Tarabeh, R.; Gupta, P.K.; Major, D.T. Benchmarking the ability of common docking programs to correctly reproduce and score binding modes in SARS-CoV-2 Protease Mpro. J. Chem. Inf. Model., 2021, 61(6), 2957-2966.
[http://dx.doi.org/10.1021/acs.jcim.1c00263] [PMID: 34047191]
[31]
Zhang, L.; Lin, D.; Kusov, Y.; Nian, Y.; Ma, Q.; Wang, J.; von Brunn, A.; Leyssen, P.; Lanko, K.; Neyts, J.; de Wilde, A.; Snijder, E.J.; Liu, H.; Hilgenfeld, R. α-Ketoamides as broad-spectrum inhibitors of coronavirus and enterovirus replication: Structure-based design, synthesis, and activity assessment. J. Med. Chem., 2020, 63(9), 4562-4578.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01828] [PMID: 32045235]

Rights & Permissions Print Cite
Article Metrics
33
2
© 2024 Bentham Science Publishers | Privacy Policy