Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against SARS-CoV2: Evidence from in silico studies
Ananta Swargiary
doi:10.21203/rs.3.rs-73308/v1
Purpose: COVID-19, caused by SARS-CoV2 virus is a contagious disease affecting millions of lives throughout the globe. Currently, there are no clinically approved drugs for SARS-CoV2 although some drugs are undergoing clinical trials. The present study investigates the binding property of ivermectin on four important drug targets, spike protein, RNA-dependent RNA polymerase, 3-chymotrypsin-and papainlike proteases of SARS-CoV2. Methods: The 3D structure of ivermectin along with known antiviral drug lopinavir, simeprevir and four nucleotides ATP, GTP, CTP, and UTP were
Ethics approval: NA Consent to participate: NA Consent for publication: Author gives the consent to publish the manuscript
References
Anand, Ziebuhr, Wadhwani, Mesters, Hilgenfeld et al., Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase, J Biomol Struct Dyn. Doi,
doi:10.1126/science.1085658Benvenuto, Giovanetti, Ciccozzi, Spoto, Angeletti et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res,
doi:10.1002/jmv.25688Canga, Prieto, Liebana, Martinez, Vega et al., The Pharmacokinetics and Interactions of Ivermectin in Humans -A Mini-review, AAPS J,
doi:10.1208/s12248-007-9000-9Chen, Yiu, Wong, Prediction of the SARSCoV-2 (2019-nCoV) 3C-like protease (3CL (pro) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates, F1000Research,
doi:10.12688/f1000research.22457.1Lv, Liu, Wang, Dang, Qiu et al., Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo, Antiviral Res,
doi:.org/10.1016/j.antiviral.2018.09.010Patrì, Fabbrocini, Hydroxychloroquine and ivermectin: A synergistic combination for COVID-19 chemoprophylaxis and treatment?, J Am Acad Dermatol,
doi:10.1016/j.jaad.2020.04.017Sharun, Dhama, Patel, Pathak, Tiwari et al., Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19, Ann Clin Microbiol Antimicrob,
doi:10.1186/s12941-020-00368-wTouret, Gilles, Barral, Nougairede, Helden et al., In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication, Sci Rep,
doi:10.1038/s41598-020-70143-6Trott, Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, e cient optimization and multithreading, J Comput Chem,
doi:10.1002/jcc.21334Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Xu, Liu, Weiss, Sg, Ding, Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design, Nucleic Acids Res,
doi:10.1093/nar/gkg916Yin, Mao, Luan, Shen, Shen et al., Structural basis for inhibition of the RNAdependent RNA polymerase from SARS-CoV-2 by remdesivir, Science,
doi:10.1126/science.abc1560Zhou, Fang, Yang, Xu, Lv et al., Identi cation of novel proteolytically inactive mutations in coronavirus 3C-like protease using a combined approach, The FASEB Journal,
doi:10.1096/fj.201901624RR{ 'institution': [{'name': 'Research Square'}],
'indexed': {'date-parts': [[2024, 4, 13]], 'date-time': '2024-04-13T15:30:20Z', 'timestamp': 1713022220401},
'posted': {'date-parts': [[2020, 9, 9]]},
'group-title': 'In Review',
'reference-count': 0,
'publisher': 'Research Square Platform LLC',
'license': [ { 'start': { 'date-parts': [[2020, 9, 9]],
'date-time': '2020-09-09T00:00:00Z',
'timestamp': 1599609600000},
'content-version': 'unspecified',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'accepted': {'date-parts': [[2020, 9, 7]]},
'abstract': '<jats:title>Abstract</jats:title>\n'
' <jats:p>Purpose: COVID-19, caused by SARS-CoV2 virus is a contagious disease '
'affecting millions of lives throughout the globe. Currently, there are no clinically approved '
'drugs for SARS-CoV2 although some drugs are undergoing clinical trials. The present study '
'investigates the binding property of ivermectin on four important drug targets, spike '
'protein, RNA-dependent RNA polymerase, 3-chymotrypsin- and papain-like proteases of '
'SARS-CoV2. Methods: The 3D structure of ivermectin along with known antiviral drug lopinavir, '
'simeprevir and four nucleotides ATP, GTP, CTP, and UTP were downloaded from PubChem database. '
'Crystal structures of proteins were downloaded from PDB database. PDB files were converted '
'into pdbqt file using AutoDock tools. After proper processing and grid formation, docking was '
'carried out in AutoDock vina. Furthermore, the co-crystallized RNA and its binding '
'interactions with RdRp were studied using various visualization tools including Discovery '
'studio.Results: Docking study showed that ivermectin is the best binding drug compared to '
'lopinavir and simeprevir. The best binding interaction was found to be -9.7kcal/mol with RdRp '
'suggesting potential inhibitor of the protein. Twenty-one amino acid residues of RdRp were '
'found to interact with ivermectin including the catalytic residue Asp760. Furthermore, '
'RNA-RdRp complex revealed that the catalytic active residues Ser759 and Asp760 of RdRp formed '
'strong interactions with RNA chain. Binding of ivermectin in the active site of RdRp make '
'clash with the nucleotides of RNA chain suggesting the possible inhibition of '
'replication.Conclusions: The present study suggests ivermectin as a potential inhibitor of '
'RdRp which may be crucial to combat the SARS-CoV2.</jats:p>',
'DOI': '10.21203/rs.3.rs-73308/v1',
'type': 'posted-content',
'created': {'date-parts': [[2020, 9, 9]], 'date-time': '2020-09-09T23:32:50Z', 'timestamp': 1599694370000},
'source': 'Crossref',
'is-referenced-by-count': 7,
'title': 'Ivermectin as a promising RNA-dependent RNA polymerase inhibitor and a therapeutic drug against '
'SARS-CoV2: Evidence from in silico studies',
'prefix': '10.21203',
'author': [ { 'ORCID': 'http://orcid.org/0000-0001-9594-3666',
'authenticated-orcid': False,
'given': 'Ananta',
'family': 'Swargiary',
'sequence': 'first',
'affiliation': [{'name': 'Department of Zoology, Bodoland University'}]}],
'member': '8761',
'container-title': [],
'original-title': [],
'link': [ { 'URL': 'https://www.researchsquare.com/article/rs-73308/v1',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://www.researchsquare.com/article/rs-73308/v1.html',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 3, 17]],
'date-time': '2021-03-17T18:46:53Z',
'timestamp': 1616006813000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.researchsquare.com/article/rs-73308/v1'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2020, 9, 9]]},
'references-count': 0,
'URL': 'http://dx.doi.org/10.21203/rs.3.rs-73308/v1',
'relation': {},
'subject': [],
'published': {'date-parts': [[2020, 9, 9]]},
'subtype': 'preprint'}
