The Binding mechanism of Ivermectin and levosalbutamol with spike protein of SARS-CoV-2
Joyanta Kumar Saha, Md. Jahir Raihan
doi:10.21203/rs.3.rs-160254/v1
In this study, we have investigated the binding mechanism of two FDA approved drugs (ivermectin and levosalbutamol) with the spike protein of SARs-CoV-2 using three different computational modeling techniques. Molecular docking results predict that ivermectin shows a large binding a nity for spike protein (-9.0 kcal/mol) compared to levosalbutamol (-4.1 kcal/mol). Ivermectin binds with GLN492, GLN493, GLY496 and TRY505 residues in the spike protein through hydrogen bonds and levosalbutamol binds with TYR453 and TYR505 residues. Using density functional theory (DFT) studies, we have calculated the binding energies between ivermectin and levosalbutamol with residues in spike protein which favor their binding are − 17.8 kcal/mol and − 20.08 kcal/mol, respectively. The natural bond orbital (NBO) charge analysis has been performed to estimate the amount of charge transfer that occurred by two drugs during interaction with residues. Molecular dynamics (MD) study con rms the stability of spike protein bound with ivermectin through RMSD and RMSF analyses. Three different computer modeling techniques reveal that ivermectin is more stable than levosalbutamol in the active site of spike protein where hACE2 binds. Therefore, ivermectin can be a suitable inhibitor for SARS-CoV-2 to enter into the human cell through hACE2.
References
Becke, Density-functional thermochemistry. III. The role of exact exchange, J Chem Phys
Berendsen, Postma, Van Gunsteren, Dinola, Haak, Molecular dynamics with coupling to an external bath, J Chem Phys
Best, Zhu, Shim, Lopes, Mittal et al., Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ1 and χ2 Dihedral Angles, J Chem Theory Comput
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Essmann, Perera, Berkowitz, Darden, Lee et al., A smooth particle mesh Ewald method, J Chem Phys
Frisch, Trucks, Schlegel, Scuseria, Robb et al., jax/output/CommonHTML/fonts/TeX
Gorbalenya, Baker, Baric, De Groot, Drosten et al., Coronaviridae Study Group of the International Committee on Taxonomy of, The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2, Nature Microbiology
Hagar, Ahmed, Aljohani, Alhaddad, Investigation of Some Antiviral N-Heterocycles as COVID 19 Drug: Molecular Docking and DFT Calculations, International Journal of Molecular Sciences
Jat, Khairwa, Levalbuterol versus albuterol for acute asthma: a systematic review and meta-analysis, Pulm Pharmacol Ther
Lee, Yang, Parr, Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density, Phys Rev B
Morse, Lalonde, Xu, Liu, Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV, ChemBioChem
Pronk, Páll, Schulz, Larsson, Bjelkmar et al., GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit, Bioinformatics
Ragia, Manolopoulos, Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies, European Journal of Clinical Pharmacology
Saha, Hossain, Ghosh, DFT study of response mechanism and selectivity of poly(3,4-ethylenedioxythiophene) towards CO2 and SO2 as gas sensor, Struct Chem
Spackman, Yu, Morton, Parker, Bond et al., Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals, Angew Chem Int Ed
Touret, Gilles, Barral, Nougairède, Van Helden et al., In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication, Sci Rep
Yang, Wang, COVID-19: a new challenge for human beings, Cell Mol Immunol
Yi, Sun, Ye, Ding, Liu et al., Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies, Cell Mol Immunol
Yuan, Wang, Zhao, Chen, Yang et al., Structure-Based High-Throughput Epitope Analysis of Hexon Proteins in B and C Species Human Adenoviruses (HAdVs), PLOS ONE
DOI record:
{
"DOI": "10.1007/s11224-021-01776-0",
"ISSN": [
"1040-0400",
"1572-9001"
],
"URL": "http://dx.doi.org/10.1007/s11224-021-01776-0",
"alternative-id": [
"1776"
],
"assertion": [
{
"group": {
"label": "Article History",
"name": "ArticleHistory"
},
"label": "Received",
"name": "received",
"order": 1,
"value": "15 January 2021"
},
{
"group": {
"label": "Article History",
"name": "ArticleHistory"
},
"label": "Accepted",
"name": "accepted",
"order": 2,
"value": "30 March 2021"
},
{
"group": {
"label": "Article History",
"name": "ArticleHistory"
},
"label": "First Online",
"name": "first_online",
"order": 3,
"value": "12 April 2021"
},
{
"group": {
"label": "Declarations",
"name": "EthicsHeading"
},
"name": "Ethics",
"order": 1
},
{
"group": {
"label": "Conflict of interest",
"name": "EthicsHeading"
},
"name": "Ethics",
"order": 2,
"value": "The authors declare no conflict of interest."
},
{
"label": "Free to read",
"name": "free",
"value": "This content has been made available to all."
}
],
"author": [
{
"ORCID": "http://orcid.org/0000-0002-5592-2577",
"affiliation": [],
"authenticated-orcid": false,
"family": "Saha",
"given": "Joyanta Kumar",
"sequence": "first"
},
{
"affiliation": [],
"family": "Raihan",
"given": "Md. Jahir",
"sequence": "additional"
}
],
"container-title": "Structural Chemistry",
"container-title-short": "Struct Chem",
"content-domain": {
"crossmark-restriction": false,
"domain": [
"link.springer.com"
]
},
"created": {
"date-parts": [
[
2021,
4,
12
]
],
"date-time": "2021-04-12T09:03:30Z",
"timestamp": 1618218210000
},
"deposited": {
"date-parts": [
[
2021,
9,
1
]
],
"date-time": "2021-09-01T11:23:05Z",
"timestamp": 1630495385000
},
"funder": [
{
"DOI": "10.13039/100004457",
"award": [
"16-008 RG/CHE/AS_I – FR3240293317"
],
"doi-asserted-by": "publisher",
"name": "The World Academy of Sciences"
}
],
"indexed": {
"date-parts": [
[
2024,
5,
3
]
],
"date-time": "2024-05-03T08:24:47Z",
"timestamp": 1714724687931
},
"is-referenced-by-count": 17,
"issue": "5",
"issued": {
"date-parts": [
[
2021,
4,
12
]
]
},
"journal-issue": {
"issue": "5",
"published-print": {
"date-parts": [
[
2021,
10
]
]
}
},
"language": "en",
"license": [
{
"URL": "https://www.springer.com/tdm",
"content-version": "tdm",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2021,
4,
12
]
],
"date-time": "2021-04-12T00:00:00Z",
"timestamp": 1618185600000
}
},
{
"URL": "https://www.springer.com/tdm",
"content-version": "vor",
"delay-in-days": 0,
"start": {
"date-parts": [
[
2021,
4,
12
]
],
"date-time": "2021-04-12T00:00:00Z",
"timestamp": 1618185600000
}
}
],
"link": [
{
"URL": "https://link.springer.com/content/pdf/10.1007/s11224-021-01776-0.pdf",
"content-type": "application/pdf",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://link.springer.com/article/10.1007/s11224-021-01776-0/fulltext.html",
"content-type": "text/html",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://link.springer.com/content/pdf/10.1007/s11224-021-01776-0.pdf",
"content-type": "application/pdf",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "297",
"original-title": [],
"page": "1985-1992",
"prefix": "10.1007",
"published": {
"date-parts": [
[
2021,
4,
12
]
]
},
"published-online": {
"date-parts": [
[
2021,
4,
12
]
]
},
"published-print": {
"date-parts": [
[
2021,
10
]
]
},
"publisher": "Springer Science and Business Media LLC",
"reference": [
{
"DOI": "10.1038/s41564-020-0695-z",
"author": "AE Gorbalenya",
"doi-asserted-by": "publisher",
"first-page": "536",
"journal-title": "Nat Microbiol",
"key": "1776_CR1",
"unstructured": "Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, Haagmans BL, Lauber C, Leontovich AM, Neuman BW, Penzar D, Perlman S, Poon LLM, Samborskiy DV, Sidorov IA, Sola I, Ziebuhr J (2020) V. Coronaviridae Study Group of the International Committee on Taxonomy of, The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 5:536–544",
"volume": "5",
"year": "2020"
},
{
"DOI": "10.1038/s41423-020-0407-x",
"author": "P Yang",
"doi-asserted-by": "publisher",
"first-page": "555",
"journal-title": "Cell Mol Immunol",
"key": "1776_CR2",
"unstructured": "Yang P, Wang X (2020) COVID-19: a new challenge for human beings. Cell Mol Immunol 17:555–557",
"volume": "17",
"year": "2020"
},
{
"DOI": "10.3390/ijms21113922",
"doi-asserted-by": "crossref",
"key": "1776_CR3",
"unstructured": "Hagar M, Ahmed HA, Aljohani G, Alhaddad OA (2020) Investigation of some antiviral N-heterocycles as COVID 19 drug: molecular docking and DFT calculations. Int J Mol Sci 21"
},
{
"DOI": "10.1016/j.antiviral.2020.104787",
"author": "L Caly",
"doi-asserted-by": "publisher",
"first-page": "104787",
"journal-title": "Antivir Res",
"key": "1776_CR4",
"unstructured": "Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM (2020) The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res 178:104787",
"volume": "178",
"year": "2020"
},
{
"DOI": "10.1038/s41423-020-0458-z",
"author": "C Yi",
"doi-asserted-by": "publisher",
"first-page": "621",
"journal-title": "Cell Mol Immunol",
"key": "1776_CR5",
"unstructured": "Yi C, Sun X, Ye J, Ding L, Liu M, Yang Z, Lu X, Zhang Y, Ma L, Gu W, Qu A, Xu J, Shi Z, Ling Z, Sun B (2020) Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies. Cell Mol Immunol 17:621–630",
"volume": "17",
"year": "2020"
},
{
"DOI": "10.1007/s00228-020-02963-4",
"doi-asserted-by": "crossref",
"key": "1776_CR6",
"unstructured": "Ragia G, Manolopoulos VG (2020) Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies. Eur J Clin Pharmacol"
},
{
"DOI": "10.1002/cbic.202000047",
"author": "JS Morse",
"doi-asserted-by": "publisher",
"first-page": "730",
"journal-title": "ChemBioChem",
"key": "1776_CR7",
"unstructured": "Morse JS, Lalonde T, Xu S, Liu WR (2020) Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. ChemBioChem 21:730–738",
"volume": "21",
"year": "2020"
},
{
"DOI": "10.3390/molecules25092071",
"doi-asserted-by": "crossref",
"key": "1776_CR8",
"unstructured": "S.S. Ahmad, M. Sinha, K. Ahmad, M. Khalid, I. Choi (2020) Study of Caspase 8 Inhibition for the Management of Alzheimer’s Disease: A Molecular Docking and Dynamics Simulation, Molecules, 25:2071."
},
{
"DOI": "10.1038/s41598-020-70143-6",
"author": "F Touret",
"doi-asserted-by": "publisher",
"first-page": "13093",
"journal-title": "Sci Rep",
"key": "1776_CR9",
"unstructured": "Touret F, Gilles M, Barral K, Nougairède A, van Helden J, Decroly E, de Lamballerie X, Coutard B (2020) In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Sci Rep 10:13093",
"volume": "10",
"year": "2020"
},
{
"DOI": "10.1016/j.pupt.2012.11.003",
"author": "KR Jat",
"doi-asserted-by": "publisher",
"first-page": "239",
"journal-title": "Pulm Pharmacol Ther",
"key": "1776_CR10",
"unstructured": "Jat KR, Khairwa A (2013) Levalbuterol versus albuterol for acute asthma: a systematic review and meta-analysis. Pulm Pharmacol Ther 26:239–248",
"volume": "26",
"year": "2013"
},
{
"DOI": "10.1063/1.464913",
"author": "AD Becke",
"doi-asserted-by": "publisher",
"first-page": "5648",
"journal-title": "J Chem Phys",
"key": "1776_CR11",
"unstructured": "Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652",
"volume": "98",
"year": "1993"
},
{
"DOI": "10.1103/PhysRevB.37.785",
"author": "C Lee",
"doi-asserted-by": "publisher",
"first-page": "785",
"journal-title": "Phys Rev B",
"key": "1776_CR12",
"unstructured": "Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789",
"volume": "37",
"year": "1988"
},
{
"DOI": "10.1007/s11224-018-1272-4",
"author": "JK Saha",
"doi-asserted-by": "publisher",
"first-page": "1427",
"journal-title": "Struct Chem",
"key": "1776_CR13",
"unstructured": "Saha JK, Hossain MS, Ghosh MK (2019) DFT study of response mechanism and selectivity of poly(3,4-ethylenedioxythiophene) towards CO2 and SO2 as gas sensor. Struct Chem 30:1427–1436",
"volume": "30",
"year": "2019"
},
{
"key": "1776_CR14",
"unstructured": "Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams FD, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ (2016) Gaussian 16, Wallingford, CT"
},
{
"DOI": "10.1063/1.448118",
"author": "HJC Berendsen",
"doi-asserted-by": "publisher",
"first-page": "3684",
"journal-title": "J Chem Phys",
"key": "1776_CR15",
"unstructured": "Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690",
"volume": "81",
"year": "1984"
},
{
"DOI": "10.1063/1.470117",
"author": "U Essmann",
"doi-asserted-by": "publisher",
"first-page": "8577",
"journal-title": "J Chem Phys",
"key": "1776_CR16",
"unstructured": "Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593",
"volume": "103",
"year": "1995"
},
{
"DOI": "10.1371/journal.pone.0032938",
"author": "X-H Yuan",
"doi-asserted-by": "publisher",
"first-page": "e32938",
"journal-title": "PLoS One",
"key": "1776_CR17",
"unstructured": "Yuan X-H, Wang Y-C, Jin W-J, Zhao B-B, Chen C-F, Yang J, Wang J-F, Guo Y-Y, Liu J-J, Zhang D, Gong L-L, He Y-W (2012) Structure-based high-throughput epitope analysis of hexon proteins in B and C species human adenoviruses (HAdVs). PLoS One 7:e32938",
"volume": "7",
"year": "2012"
},
{
"DOI": "10.1093/bioinformatics/btt055",
"author": "S Pronk",
"doi-asserted-by": "publisher",
"first-page": "845",
"journal-title": "Bioinformatics",
"key": "1776_CR18",
"unstructured": "Pronk S, Páll S, Schulz R, Larsson P, Bjelkmar P, Apostolov R, Shirts MR, Smith JC, Kasson PM, van der Spoel D, Hess B, Lindahl E (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29:845–854",
"volume": "29",
"year": "2013"
},
{
"DOI": "10.1021/ct300400x",
"author": "RB Best",
"doi-asserted-by": "publisher",
"first-page": "3257",
"journal-title": "J Chem Theory Comput",
"key": "1776_CR19",
"unstructured": "Best RB, Zhu X, Shim J, Lopes PEM, Mittal J, Feig M, MacKerell AD (2012) Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone ϕ, ψ and side-chain χ1 and χ2 dihedral angles. J Chem Theory Comput 8:3257–3273",
"volume": "8",
"year": "2012"
}
],
"reference-count": 19,
"references-count": 19,
"relation": {
"has-preprint": [
{
"asserted-by": "object",
"id": "10.21203/rs.3.rs-160254/v1",
"id-type": "doi"
}
]
},
"resource": {
"primary": {
"URL": "https://link.springer.com/10.1007/s11224-021-01776-0"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "The binding mechanism of ivermectin and levosalbutamol with spike protein of SARS-CoV-2",
"type": "journal-article",
"update-policy": "http://dx.doi.org/10.1007/springer_crossmark_policy",
"volume": "32"
}