COMPARATIVE ANALYSIS OF SMALL MOLECULES AND NATURAL PLANT COMPOUNDS AS THERAPEUTIC INHIBITORS TARGETING RdRp AND NUCLEOCAPSID PROTEINS OF SARS COV 2: AN IN SILICO APPROACH

PAVAN KUMAR POLEBOYINA; SMITA C PAWAR

doi:10.22159/ajpcr.2023.v16i10.48095

Authors

PAVAN KUMAR POLEBOYINA Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, Telangana, India. https://orcid.org/0000-0003-0393-3917
SMITA C PAWAR Department of Genetics and Biotechnology, University College of Science, Osmania University, Hyderabad, Telangana, India.

DOI:

https://doi.org/10.22159/ajpcr.2023.v16i10.48095

Keywords:

RNA-dependent RNA polymerase, N protein, Severe acute respiratory syndrome coronavirus disease-2, Coronavirus disease, Natural plant compounds, Small molecules, Molecular docking

Abstract

Objective: Coronavirus disease 2019 (COVID-19) is a virus-borne infection caused by the severe acute respiratory syndrome coronavirus disease-2 (SARS-CoV-2) virus. Nucleocapsid protein and RNA-dependent RNA polymerase (RdRp) activity in viral structural membrane, transcription, and replication have been identified as desirable targets for the development of novel antiviral strategies. The SARS-COV-2 N protein binds to the viral genome to promote the precise folding of the hammerhead ribozyme, preventing ineffective RNA confirmations, and directs them into a helical capsid shape or ribonucleoprotein complex, which is vital for viability. RNA synthesis requires RdRp to form phosphodiester bonds based on the RNA template. SARS-CoV-2 RNA synthesis, transcription, and replication depend on RdRp’s complex with nsp7 and nsp8.

Methods: Our study targeted SARS-COV-2 RdRp and N proteins with natural plant compounds and small molecules. Hyperchem software optimized their structures geometrically and energetically. Based on MolDock, Rerank, and H-bonding energy, the best ligands were selected using the Molegro virtual docker.

Results: In our analysis, we have identified nine compounds against N protein and seven compounds against RdRp protein that had more potent inhibitory effects with the lowest MolDock scores. The top 6 (Alpha solanine, Betanin, cairicoside I, Ginsenoside rb 1, Naringin, Polyphyllin I) compounds that have better inhibitory effects against both proteins.

Conclusion: We conclude that the top six compounds have greater inhibitory efficacy against N and RdRp protein than other compounds. However, in vitro and in vivo experimental studies, as well as clinical trials, are required to achieve the desired result.

Downloads

Download data is not yet available.

References

Park SE. Epidemiology, virology, and clinical features of severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2; coronavirus Disease-19). Clin Exp Pediatr 2020;63:119-24. doi: 10.3345/ cep.2020.00493, PMID 32252141, PMC7170784

Gajjar ND, Dhameliya TM, Shah GB. In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis. J Mol Struct 2021;1239:130488. doi: 10.1016/j.molstruc.2021.130488, PMID 33903778

Mandal M, Chowdhury SK, Khan AA, Baildya N, Dutta T, Misra D, et al. Inhibitory efficacy of RNA virus drugs against SARS-CoV-2 proteins: An extensive study. J Mol Struct 2021;1234:130152. doi: 10.1016/j.molstruc.2021.130152, PMID 33678903

COVID-19 Infection: Origin, Transmission, and Characteristics of Human Coronaviruses. Elsevier Enhanced Reader. Available from: https://reader.elsevier.com/reader/sd/pii/S2090123220300540?token=6 ddbb062f469ed88128e0bea7af62a17089cb020930ab21f56295339e53 4532e592a1609bc5109784E9655941e42ac33&originregion=eu-west- 1&origincreation=20210606200221 [Last accessed on 2021 Jun 07].

Mahrosh HS, Mustafa G. An in silico approach to target RNA-dependent RNA polymerase of COVID-19 with naturally occurring phytochemicals. Environ Dev Sustain 2021;23:16674-87. doi: 10.1007/s10668-021-01373-5, PMID 33841038

Zhu W, Chen CZ, Gorshkov K, Xu M, Lo DC, Zheng W. RNA-dependent RNA polymerase as a target for COVID-19 drug discovery. SLAS Discov 2020;25:1141-51. doi: 10.1177/2472555220942123, PMID 32660307

Biswal M, Diggs S, Xu D, Khudaverdyan N, Lu J, Fang J, et al. Two conserved oligomer interfaces of NSP7 and NSP8 underpin the dynamic assembly of SARS-CoV-2 RdRP. Nucleic Acids Res 2021;49:5956-66.

Ramanathan A, Pullara F, Kumar TD, Shaikh N, Kumar US, Priya Doss GC, et al. Structure-based virtual screening to identify novel potential compound as an alternative to remdesivir to overcome the RdRp protein mutations in SARS-CoV-2. Front Mol Biosci 2021;1:645216.

Machitani M, Yasukawa M, Nakashima J, Furuichi Y, Masutomi K. RNA-dependent RNA polymerase, RdRP, a promising therapeutic target for cancer and potentially COVID-19. Cancer Sci 2020;111:3976-84. doi: 10.1111/cas.14618, PMID 32805774

Jiang Y, Yin W, Xu HE. Since January 2020 Elsevier has Created a COVID-19 Resource Centre with Free Information in English and Mandarin on the Novel Coronavirus COVID-19. The COVID-19 Resource Centre is Hosted on Elsevier Connect, the Company’s Public News and Information. Netherlands: Elsevier; 2020.

Aftab SO, Ghouri MZ, Masood MU, Haider Z, Khan Z, Ahmad A, et al. Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach. J Transl Med 2020;18:275. doi: 10.1186/s12967-020-02439-0, PMID 32635935

Tugaeva KV, Hawkins DE, Smith JL, Bayfield OW, Ker DS, Sysoev AA, et al. The mechanism of SARS-CoV-2 nucleocapsid protein recognition by the human 14-3-3 proteins. J Mol Biol 2021;433:166875. doi: 10.1016/j.jmb.2021.166875, PMID 33556408

Batra M, Tian R, Zhang C, Clarence E, Sacher CS, Miranda JN, et al. Role of IgG against N-protein of SARS-CoV2 in COVID19 clinical outcomes. Sci Rep 2021;11:3455. doi: 10.1038/s41598-021-83108-0, PMID 33568776

Gao T, Gao Y, Liu X, Nie Z, Sun H, Lin K, et al. Identification and functional analysis of the SARS-COV-2 nucleocapsid protein. BMC Microbiol 2021;21:58. doi: 10.1186/s12866-021-02107-3, PMID 33618668

Tatar G, Ozyurt E, Turhan K. Computational drug repurposing study of the RNA binding domain of SARS-CoV-2 nucleocapsid protein with antiviral agents. Biotechnol Prog 2021;37:e3110. doi: 10.1002/ btpr.3110, PMID 33314794

Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: A powerful approach for structure-based drug discovery. Curr Comput Aid Drug Des 2011;7:146-57. doi: 10.2174/157340911795677602, PMID 21534921

RCSB PDB: Homepage. Available from: https://www.rcsb.org [Last accessed on 2021 Jun 24].

Available from: https://pubchem.ncbi.nlm.nih.gov [Last accessed on 2021 Jun 24].

Daoud I, Melkemi N, Salah T, Ghalem S. Combined QSAR, molecular docking and molecular dynamics study on new acetylcholinesterase and butyrylcholinesterase inhibitors. Comput Biol Chem 2018;74:304-26. doi: 10.1016/j.compbiolchem.2018.03.021

Bitencourt-Ferreira G, de Azevedo WF Jr. Molegro virtual docker for docking. Methods Mol Biol 2019;2053:149-67. doi: 10.1007/978-1- 4939-9752-7_10, PMID 31452104

Aps M. Molegro Data Modeller User Manual MDM; 2009. 2.0 for Windows, Linux, and Mac OS X. Vol. 2007.

Sadeghi F, Afkhami A, Madrakian T, Ghavami R. Computational study to select the capable anthracycline derivatives through an overview of drug structure-specificity and cancer cell line-specificity. Chem Pap 2021;75:523-38. doi: 10.1007/s11696-020-01321-z

Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C. Comparison of multiple amber force fields and development of improved protein backbone parameters. Proteins 2006;65:712-25. doi: 10.1002/prot.21123, PMID 16981200

Swiss PD. Viewer - Home. Available from: https://spdbv.vital-it.ch [Last accessed on 2021 Jul 08].

Bouchagra S, Benamia F, Djeghaba Z. Docking studies of (-)-epigallocatechin-3-gallate: A potential noncompetitive pancreatic lipase inhibitor. Res J Pharm Biol Chem Sci 2016;7:2493-505.

Singh SP, Deb CR, Ahmed SU, Saratchandra Y, Konwar BK. Molecular docking simulation analysis of the interaction of dietary flavonols with heat shock protein 90. J Biomed Res 2015;30:67-74. doi: 10.7555/ JBR.29.20130158, PMID 26423731, PMC4726836

PKCSM. Available from: https://biosig.unimelb.edu.au/pkcsm/ prediction [Last accessed on 2021 Jun 07].

Swiss ADME. Available from: https://www.swissadme.ch [Last accessed on 2021 Jul 03].

Molinspiration. Cheminformatics. Available from: https://www. molinspiration.com [Last accessed on 2021 Jul 03].

ERRAT - Help - DOE-MBI Structure Lab UCLA. Available from: https:// servicesn.mbi.ucla.edu/errat/help [Last accessed on 2021 Jun 07].

Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Crystallogr 1993;26:283-91. doi: 10.1107/S0021889892009944

PDBsum Entry: 6m3m. Available from: https://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/getpage.pl [Last accessed on 2021 Jun 07].

Thomsen R, Christensen MH. MolDock: A new technique for high-accuracy molecular docking. J Med Chem 2006;49:3315-21. doi: 10.1021/jm051197e, PMID 16722650

Copeland RA. Conformational adaptation in drug-target interactions and residence time. Future Med Chem 2011;3:1491-501. doi: 10.4155/ fmc.11.112, PMID 21882942

Guan L, Yang H, Cai Y, Sun L, Di P, Li W, et al. ADMET-score-a comprehensive scoring function for evaluation of chemical drug-likeness. Medchemcomm 2019;10:148-57. doi: 10.1039/c8md00472b, PMID 30774861