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Catechin and Curcumin interact with corona (2019-nCoV/SARS-CoV2) viral S protein and ACE2 of human cell membrane: insights from Computational study and implication for intervention

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The recent outbreak of the coronavirus (2019n-CoV) is an unprecedented threat for human health throughout the globe. In this regards development of a suitable intervention is the need of the hour. The viral spike protein (S-Protein) and the cognate host cell receptor ACE2 can prove to be effective. Here, through computational approaches we have reported two polyphenols, Catechin and Curcumin which have dual binding affinity i.e both the molecule binds to viral S-protein and as well as ACE2. Catechin binds with S-protein and ACE2 with binding energy of -10.5 Kcal/mol and -8.9 Kcal/mol, respectively. Catechin binds with a greater affinty than that of curcumin which has a binding energy of -7.9Kcal/mol and - 7.8Kcal/mol for S-protein and ACE2, respectively. While curcumin gets bound directly to receptor binding domain (RBD) of viral S-protein, catechin binds to near proximity of RBD sequence of S-protein. Molecular simulation study demonstrates that curcumin directly binds with RBD site of S-protein during 40-100ns. In contrast, catechin binds with S-protein near the RBD site and causes fluctuation in the amino acids present in the RBD and it’s near proximity. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols, for therapeutic/preventive intervention.
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Preprint:Pleasenotethatthisarticlehasnotcompletedpeerreview.
CatechinandCurcumininteractwithcorona(2019-
nCoV/SARS-CoV2)viralSproteinandACE2ofhuman
cellmembrane:insightsfromComputationalstudy
andimplicationforintervention
CURRENTSTATUS:UNDERREVIEW
AtalaB.Jena
CentreOfExcellenceInIntegratedOmicsandComputationalBiology,UtkalUniversity
NamrataKanungo
PostGraduateDepartmentofBiotechnology,UtkalUniversity
VinayakNayak
PostGraduateDepartmentofBiotechnology,UtkalUniversity
G.B.N.Chainy
PostGraduateDepartmentofBiotechnology,UtkalUniversity
JagneshwarDandapat
CentreOfExcellenceInIntegratedOmicsandComputationalBiologyandPostGraduate
DepartmentofBiotechnology,UtkalUniversity
jd.biotech@utkaluniversity.ac.inCorrespondingAuthor
DOI:
10.21203/rs.3.rs-22057/v1
SUBJECTAREAS
Pharmacodynamics
KEYWORDS
Coronavirus,Curcumin,Catechin,MolecularDocking,Simulation,polyphenols
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Abstract
Therecentoutbreakofthecoronavirus(2019n-CoV)isanunprecedentedthreatforhumanhealth
throughouttheglobe.Inthisregardsdevelopmentofasuitableinterventionistheneedofthehour.
Theviralspikeprotein(S-Protein)andthecognatehostcellreceptorACE2canprovetobeeffective.
Here,throughcomputationalapproacheswehavereportedtwopolyphenols,CatechinandCurcumin
whichhavedualbindingaffinityi.eboththemoleculebindstoviralS-proteinandaswellasACE2.
CatechinbindswithS-proteinandACE2withbindingenergyof-10.5Kcal/moland-8.9Kcal/mol,
respectively.Catechinbindswithagreateraffintythanthatofcurcuminwhichhasabindingenergy
of-7.9Kcal/moland-7.8Kcal/molforS-proteinandACE2,respectively.Whilecurcumingetsbound
directlytoreceptorbindingdomain(RBD)ofviralS-protein,catechinbindstonearproximityofRBD
sequenceofS-protein.Molecularsimulationstudydemonstratesthatcurcumindirectlybindswith
RBDsiteofS-proteinduring40-100ns.Incontrast,catechinbindswithS-proteinneartheRBDsite
andcausesfluctuationintheaminoacidspresentintheRBDandit’snearproximity.Inconclusion,
thiscomputationalstudyforthefirsttimepredictsthepossibilityofabovetwopolyphenols,for
therapeutic/preventiveintervention.
Introduction
Coronaviruses(2019-nCoV/SARS-CoV2)belongingtofamilyCoronaviridae,aresinglestranded,
enveloped,positivesenseRNAvirusesmostlyinfecting(birdsandmammalsandamatterofglobal
concern1,2.WHOdeclareditpandemicduetoitshighrateoftransmissionandunavailabilityof
specificvaccineormedicationtotreatit3.PhylogeneticallySARSCoV2belongstoorder
Nidovirales4andgroupedunderBetacoronavirus,withagenomesizeof~30kilobases,whichcodes
fordifferentstructuralandaccessoryproteins4,5.Thegeneralmorphologyofcoronavirusincludes
differentstructuralproteinssuchasspike(S)protein,envelope(E)protein,membrane(M)protein
andthenucleocapsid(N)protein6.Coronavirusinvadeshumancellsthroughbindingofitsdistinct
surfacespikeprotein(glycoproteininnature)withareceptorprotein(s)presentonthemembraneof
humancells.Thismediatesreceptorattachmentandviral-hostcellmembranefusion(Fig.1).TheS
proteinisatransmembraneproteinwithN-exoandC—endoterminals.TheNterminalS1subunit
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containsReceptorBindingDomain(RBD)whiletheCterminalS2subunitinducesmembranefusion7
(Suppl.Fig.S1).FusionofviruswithhumancellsisresultedduetothebindingofS1subunitofviral
proteinStohumancellreceptors7,8.Ontheotherhand,consequentuponendocytosisofthevirus,
theS2subunitwhichischaracterisedbyHeptadRepeats(HR)regionsthatassemblesintoanintra-
hairpinhelicalstructurewithsixhelixbundlepromotesthemembranefusionprocessinsidethehost
cell9,10.Inaveryrecentstudy,Luetal.,2020haveobservedthatexternalsubdomainofS-
glycoproteinof2019-NCoVRBDismoresimilartothatofSARS-CoV2,whichsuggeststhatthisvirus
alsotargetAngiotensinConvertingEnzyme2(ACE2),amonomericmembraneboundproteinof
humancells11.Therefore,itispresumedthatACE2,thecognatereceptorofcoronaviruspresentin
thehostcellscanalsobeaspecifictargettopreventtheviralentry12.
Severalrecentstudieshavesuggestedthatnaturalpolyphenoliccompoundslikecatechins(GTCs;
fromgreentea)andcurcumin(diferuloylmethane;fromturmeric)haveantiviralactivitiesagainsta
broadspectrumofvirusessuchasHumanImmunodeficiencyVirus(HIV),HerpesSimplexVirus,
InfluenzaVirus,HepatitisBandCViruses(HBVandHCVrespectively)13,Adenovirus,Zikavirus14,
Chikungunyavirus(CHIKV)15.Diversemechanismshavebeensuggestedtoexplaintheantiviral
activitiesofboththepolyphenoliccompounds.Forexample,GTCshavebeendocumentedtobea
potentialsuppresserofviralentryanditsreplication16–20whilecurcuminhasbeendemonstratedasa
potentinhibitorofmonophosphatedehydrogenasearatelimitingenzymeinthedenovosynthesisof
guaninenucleotide21.Further,ithasalsobeenobservedthatGTCsandcurcumininhibitthe
expressionofACE2,asevidentfromanimalstudies22,23.
Althoughcatechinandcurcuminhavebeenreportedtobindwithvariousproteinsofviralandhuman
origin,tilldatenodataisavailablefortheirinteractionwithSproteinofthecoronavirusandits
cognatereceptor,ACE2ofhostcell.Withthisbackdrop,thepresentstudyhasbeendesignedto
examineinteractionofcatechinandcurcuminwithSproteinofthevirusanditscognatereceptorACE
2ofhostcellemployingcomputationalmethods.Computationalapproaches(Moleculardockingand
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simulation)arethefirstandforemostchoiceofscientiststoprophecyapparentbindingmodesand
affinitiesofligandsformacromoleculesbeforeexperimentalstudieswhichareindeedexpensiveand
timeconsuming.Inaddition,improvementofspeed,reliabilityandaccuracyofcomputationaldocking
methodsinlastfewyearsmadeitasuitablechoicetodesignstructure-baseddrugs.Thepresent
studyincorporatesresultsofmoleculardockingofcatechinandcurcuminwiththeProteinSofcorona
virusaswellasthecomparativebindingaffinityoftheabovephytochemicalswithACE2ofhostcella
cognatereceptorforviralS-protein.
MaterialsAndMethods
Sequenceanalysis
ThecryoEMstructureof2019-nCoVS-protein(PDBID—6vsb)andX-RaydiffractionstructureofACE2
(PDBID—1r42)withresolutionof3.46A0and2.2Årespectively,wereretrievedfromPDBdatabase.
TheFASTAsequenceofS-proteinof2019-nCoV,HCoV-229E,MERS-CoV,HCoV-NL63,SARS-CoVwere
alsoretrievedformultiplesequencealignmentanalysis.Thealignmentresultsof2019-nCoVportrayed
thatallthethreechainsofS-proteinhaveidenticalaminoacidsequences.Therefore,onlyonechain
wastakenforsecondarystructureanalysisandpredictionofphysicochemicalproperties.
Phylogeneticanalysis
FASTAsequenceofS-proteinwasretrievedfromPDBdatabaseandevolutionaryanalysisofgenetic
distanceanddiversitywereconductedbyMEGA-X.AnalysiswasaccomplishedusingtheSubstitution
ModelJones-Taylor-Thornton(JTT)24andstandarderrorestimate(s)wereobtainedbyabootstrap
procedure(1000replicates).ThephylogenetictreewasproducedbyMaximumLikelihoodstatistical
method.
MoleculardockinganalysisbetweenS-proteinand
ACE2withCatechinandCurcumin
EvaluationofbindingfreeenergyofS-proteinandACE2withcatechinandcurcuminwasdone
throughmoleculardockingprogramAutoDock4.ThecanonicalSMILESidofcatechin(Catechin-
Gallocatechin-Catechin)andcurcuminwereobtainedfromPubChemdatabase
(https://pubchem.ncbi.nlm.nih.gov/).Conversionto3DstructuresweredoneusingCHIMERA
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programme.BindingaffinityofS-proteinandACE2withcatechinandcurcuminwereexaminedusing
Vina1.1.2.Variousparameterssuchasbindingaffinity,receptorsinteractingatom,receptorpocket
atom,receptorligandinteractionsite,atomiccontactenergy(ACE)andsideaminoacidresidueswere
studiedtorecognisethebindingsiteofS-proteinandACE2.Theresultsofdockingwerevisualised
andanalysedbyDiscoveryStudioVisualizer.
Molecularsimulation
VirtualScreeningandenergyminimization
Thechemicallyunstandardized2Dstructuresofligands,curcuminandcatechinweretakenupfrom
PubChemdatabase(https://pubchem.ncbi.nlm.nih.gov/).Ligandfilescanbeswitchedtoproperly
standardisedandextrapolated3DstructuresbyLigPep.Thesestructurescanbescreenedvirtually.
LigPrepplaysamajorroleinconversionof3Dstructurestoconsequentlylowerenergystructures
whichcanbeusedbyGlideandQikPropprograms.Thisminimisationofstructuresisdoneusing
OPLS3eforcefield.Eachinputstructuregeneratesmultipleoutputstructuresduetodifferent
stereochemistry,protonationstates,tautomer’sandringconformations.Intheligandoutputfile
specificationsaremadeforproductionofonelowenergyringconformationperligand..Grid-based
LigandDockingwith
Energetics(GLIDE)moduleinSchrodingersoftwarewasusedfortheformationofS-protein-Curcumin
andS-protein-Cathechincomplex.Desmondsoftwarewasusedforcarryingoutmoleculardynamics
simulations,RootMeanSquareDeviations(RMSD)andatomicfluctuationthroughRootMeanSquare
Fluctuation(RMSF)studies.Forconductingexplicitsolventsimulationswithperiodicmarginal
conditions,differenttoolssuchascubic,orthorhombic,truncatedoctahedron,rhombicdodecahedron
andotherarbitrarysimulationboxesareused.
Hereinthisstudy,MDsimulationswereconductednotablyforthetoptwoidentifiedhitstoanalyse
thestabilityoftheligandreceptorcomplexfor100ns.Stabilityofdockedcomplexes2019-nCoVspike
glycoprotein-Curcuminand2019-nCoVspikeglycoprotein-Catechinaresimulatedtill100nssimulation
timebyperformingMolecularDynamics(MD)simulationsusingsystembuilderofDesmond
implementedinMaestro12.0withOPLS–3forcefield.Neutralisationofthedockedcomplexwasdone
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bytheadditionof4Na+ionsand1.137mMconcentrationofNa+ionsintothesystemforS-protein
andcurcumin.Similarly,6Na+ionsand1.706mMconcentrationofNa+ionsforneutralisationofS-
proteinandCatechin.
Thedecreaseinthepotentialenergyduringthe100nsincaseofbothCatechin-S-protein,Curcumin-
S-proteincomplexesrevealedthatthesystemisstable.Analysisofdifferentconformationsacquired
overthesimulationperiodof100nsisdone.Forthecomputationofaveragechangeinthe
displacementofselectedatomsinaparticularframewithrespecttoreferenceframe,Rootmean
squaredeviation(RMSD)isestimatedfortheproteinandligandfor100nssimulationtrajectory.
Results&Discussion
Structuralanalysis
Predictionofsecondarystructureof2019-nCoVS-proteinhasbeendoneusingSOPMA(SelfOptimised
PredictionMethodwithAlignment).TheS-proteincontains1288aaresiduescomprising350αhelices
(27.17%),312β-turns(9.08%),509randomcoils(39.52%).ThroughExPASyProtParam,thetotal
numberofnegativelycharged(Asp+Glu)andpositivelychargedresidues(Arg+Lys)were
determinedtobe112and100,respectively.Thealiphaticindexwasfoundtobe81.58.TheGRAVY
(GrandAverageofHydropathicity)scoredto–0.163.Theinstabilityindexwascomputedtobe31.58.
Thesefeaturesclassifytheproteinasstable.Itwasalsorevealedthroughcomputationalstudiesthat
thehalf-lifeofS-proteinismaximumincaseofmammals(mammalianreticulocytes-30hours)than
incaseofyeast(>20hours)andbacteria(E.Coli->10hours).
Structurealignment
SuperimpositionofstructuresofS-proteinsof2019-nCoVandSARS-CoVwasevaluatedbyTM-align
(https://zhanglab.ccmb.med.umich.edu/TM-align/)forcomparativestructuralstudies.Thesetwo
viruseswereconsideredforStructure-Structuresuperimpositionduetomaximumsequencesimilarity.
Fromthisstudy,itwasobservedthroughstructuralalignmentthat2019-nCoVandSARS-CoVonly
differinRBDfragmentandremainingpartofthestructureisidentical(Suppl.fig.S2).Fromthe
structurealignmentandphylogeneticanalysis,itwasobservedthatSARS-CoVisanancestorofthe
newlyupsurgevirus2019-nCoV.However,somechangeswereobservedintheRBDfragmentof
7
2019-nCoVcomparedtoSARS-CoV.
Phylogeneticanalysis
2019-nCoVsharesthehighestsequenceidentity(73.9095%)withSARS-CoVandthelowestsimilarity
inaminoacidsequencewasobservedwithHCoV–229E(10.6077%).Similarly,thesequenceidentityis
intermediatei.e22.9037%and18.5559%withMERS-CoV,HCoV-
NL63,respectively.Phylogenetictreein(Suppl.Fig.S3)showsthat2019-nCoVandSARS-CoVhave
sameOTU(OperationalTaxonomicUnit)duetothehighestsequencesimilarity.
Moleculardockinganalysis
ThebindingmodesofcurcuminandcatechinwithS-proteinandACE2werestudiedthrough
AutodockVina1.1.2.ThebindingenergyofS-proteinwithcatechinandcurcuminscoredtobe–
10.5Kcal/moland–7.9Kcal/molrespectively(Table1).ThebindingaffinityofcurcuminwithACE2was
notedtobe–7.8Kcal/molwhereasthatofcatechinwasfoundtobe-8.9Kcal/mol(Table2).Fromthe
dockingscores,itcanbededucedthatbothcatechinandcurcuminhavestrongbindingaffinitywith
S-proteinaswellasACE2.AlthoughVanderWaalsforce,conventionalhydrogenbondsandcarbon
hydrogenbondsfacilitatesbindingbetweenligands(curcuminorcatechin)andS-protein,aminoacid
residuesoftheproteinthatparticipateforsuchinteractionsfordifferentbondsvariesbetween
curcuminandcatechin(Fig.2and3).Moleculardockingexperimentsshowedtheaffinityorbinding
capacityofcurcuminandcatechinwithS-proteinaswellasACE2.Italsoprovidedtheevidencethat
catechinbindswithgreateraffinitythancurcumin
MolecularSimulationanalysis
TheresultsfromMolecularSimulationdatathrowalightontheinteractionofcurcuminwithS-protein.
ItwasobservedthatinteractionbetweencurcuminandS-proteinexistedoverthetimespanof100ns
butsubstantialinteractionwasseenduringthesimulationtimeof40nsto100ns(Fig.4).Local
changesalongtheproteinchainwerecharacterisedthroughRootMeanSquareFluctuation(RMSF).
TheplotindicatescurcuminpossessestheabilitytocausefluctuationofallaminoacidsofSprotein
(SupplFig.S4).ProteinandligandinteractionwasstrongatRBDsiteofS-proteinfrom40nsto90ns
(Suppl.Fig.S6).RBDsiteofS-proteinare
8
linkedwithketogroupofcurcuminwithstrongaffinityataminoacidLeu–335throughhydrophobic
bonds.Interactionwiththisaminoacidoccursfor40%ofthesimulationtime(Fig.5).Molecular
simulationstudiesfavourdockingstudieswhichstatethateventhoughcatechinhashighbinding
energywithS-protein,curcuminbindsdirectlytotheRBDoftheS-proteinwithgreateraffinity.Atthe
sametime,catechinisseentocausegreaterfluctuationinaminoacidsneartheRBDsite.
TheRBDfragmentof2019-nCoVspansfrom319–591S-residues25.Fromourstudiesitisdeduced
thatcurcumindirectlybindstoaminoacidsinthisregionLeuC:546,GlyC:548,PheC:541,AspC:571,
AlaC:570,ThrC:572,ThrC:547,ThrC:573whereascatechinbindstotheS-proteininthenear
proximityofRBDfragmenttoGlnB:314,GluB:309,LysB:310,GlyB:311,LysB:304,TyrB:313,Thr
B:302,IleB:312,LeuB:303andIleB:312residues(Table1).
TheaveragechangeindisplacementofatomsinallframeswasrecordedthroughRootMeanSquare
Deviation(RMSD).TheaverageRMSDisobtainedtobe18Åand10ÅforS-protein-CurcuminandS-
protein-catechincomplexrespectively.RMSDplotdepictedthebindingRMSDplotdepicted
theinteractionofS-proteinandcatechinwhichindicatetheirrigidinteractionbetween10–20ns
simulationtimeoutof100nstrajectory(Fig.6).MaximumstructuralfluctuationofS-proteinwas
observedinbetween300–500aminoacidsandafter1000aminoacidsresidues(SupplFig.S5).The
abovedatasupportsthatS-proteinandcatechininteractionoccurswithaminoacidsofS-proteinnear
theRBDsite(319aa–591aa)25.AminoacidresiduesArg–634andVal–635neartheRBDsiteofS-
proteinhavestrongeraffinitytowardshydroxylgroupofcatechinwith54%and35%,respectively,out
of100nssimulationtrajectory(Suppl.Fig.S7).
ThebindingaffinityofcurcuminwithACE2wasnotedtobe–7.8Kcal/molwhereasthatofcatechin
wasfoundtobe–8.9Kcal/mol.ThebindingofcurcuminorcatechinwithACE2includesconventional
hydrogenBond,carbon-hydrogenbondandPi-Sigmainteractions.Theaminoacidresiduesofthe
proteinthattakepartinaboveinteractionvaryforbothligands(Suppl.Fig.S8andS9,Table.2).
TheseresultsdepictedthatcurcuminandcatechinbindtoS-proteinatthesitewhereitwasknownto
getinvolvedinhostcellbinding.Similarly,itwasalsoseenthatthesemoleculesattachtothosesites
9
ofACE2whichwereinvolvedinservingamediumofviralentry.Thus,itisapparentfromthepresent
studythatviralinfectioncanbepreventedbyuseofcurcuminandcatechin.Thiswouldratherserve
dualinhibitorymachinerybyblockinghostcellreceptortovirusandviralproteinentry.Moreover,
thesetwopolyphenols(Curcuminancatechin)arepotentimmunostimulantandhavebeenreported
toinduceautophagy,anotherimportantmechanismofviralclearance13,26.Therefore,availabilityof
curcuminandcatechinmayfacilitatealldifferentmechanismssimultaneouslyandtherebypromote
eliminationorneutralisationofviralinfection.
Conclusion
Thepandemicnovelcoronavirushascreatedastarklandscapeinthesocial,healthandeconomic
sphere.Thelethalityofthevirushastakenmanylives.Thereisurgencytocurbthewidespread
outbreakof2019-nCoV.Ourresearchviainsilicoapproachindicatesthatcurcuminandcatechincan
beusedaspotentialmoleculestodevelopdrugstopreventtheviralinfection.
Declarations
Acknowledgements
AuthorsarethankfultotheWorldBank-OHEPEEforsupportingCentreofExcellenceinIntegratedin
OmicsandComputationalBiology,UtkalUniversity.SupportfromDBTGovernmentofIndia,New
DelhitoDepartmentofBiotechnology,UtkalUniversityisgratefullyacknowledged.Authorsare
gratefultothehonourableVicechancellor,UtkalUniversityforhisinspirationtodevelopthis
manuscript.WearethankfultoMr.VinodDevaraji,ApplicationScientist,schrodinger,Indiaforhis
inputs.
ConflictofInterest:Authorsdeclarenoconflictofinterest.
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Tables
Table:1;Thebindingenergy,typesofInteractionandaminoacidsinvolvedin
interactioninS-Proteinof2019-nCoVwithCurcuminandCatechine.
13
Protein Ligand Binding
Affinity Interaction AA:Name;
ChainName;AA:
No;
S-protein Curcumin -7.9 Vanderwaals: LeuC:546,GlyC:548,
PheC:541,
AsnA:856,LeuA:997,
SerA:967,
AspC:571,AlaC:570,Val
A:976,ThrC:572
ConventionalHydrogen
Bond: AspA:979,Thr
C:547,ArgA:1000,Ser
A:975
Carbon-Hydrogen
Bond:
ThrC:573,AsnA:978,
CysA:743
Pi-Donor
HydrogenBond:
ThrC:573,Asn
A:978,CysA:743
Pi-Sigma: LeuA:966
S-protein Catechine -10.5 Vanderwaals: GlnB:314,GluB:309,
LysB:310,
GlyB:311,IleB:664,Lys
C:733,
LeuC:861,AspB:950,Gly
C:769,
AlaC:766,LysB:304,
ThrC:761
ConventionalHydrogen
Bond:
TyrB:313,ThrC:768,
AsnC:764,
ThrB:302,GlnB:954,
AspC:775
Carbon-
HydrogenBond:
IleB:312
Pi-Sigma: ThrC:768,Val
C:772,LeuB:303
Pi-Cation: ArgC:765
Pi-Alkyl: IleB:312,Pro
B:665,ArgC:765
14
Table:2;Thebindingenergy,typesofInteractionandaminoacidsinvolvedin
interactioninHumanACE-2receptorwithCurcuminandCatechine.
Receptor Ligand BindingAffinity Interaction AA:Name;
ChainName;AA:
No;
ACE2 Curcumin -7.8 Conventional
HydrogenBond:
GlnA:102,TrpA:566
Carbon-Hydrogen
Bond:
GlnA:98
Pi-Alkyl: ValA:209,ProA:565,
ValA:212
Pi-Sigma: LeuA:95
ACE2 Catechine -8.9 Conventional
HydrogenBond:
SerA:43,AspA:382
Carbon-Hydrogen
Bond:
HisA:401,TrpA:69,
SerA:47
Pi-Alkyl: MetA:62,ArgA:393
Pi-Pistacked: HisA:401,PheA:390,
PheA:40
Pi-PiT-shaped: HisA:401,PheA:390,
PheA:40
Unfavourable
Donor-Donor: ArgA:393
Figures
15
Figure1
BindingofviralS-proteinwiththeACE2cellularreceptor.
16
Figure2
DockedposeofCurcumininthebindingpocketofS-Protein.(a)2Drepresentationof
CurcuminandS-Proteininteraction.(b,c)CurcuminbindwithS-ProteininHydrophobic
condition.(d)ParticipatingAminoacidsinbindingpocketofS-Protein.
17
Figure3
DockedposeofCatechininthebindingpocketofS-Protein.(a)2Drepresentationof
CatechinandS-Proteininteraction.(b,c)CatechinbindwithS-ProteininHydrophobic
condition.(d)ParticipatingAminoacidsinbindingpocketofS-Protein.
18
Figure4
RootMeanSquareDeviation(RMSD)plotforinteractivecomplexofCurcuminandS-Protein
during0–100nsofmoleculardynamicsimulation.
Figure5
IllustrationofbondsbetweenAminoacidresiduesofS-ProteinandCurcuminduringtheir
interaction.
19
Figure6
RootMeanSquareDeviation(RMSD)plotforinteractivecomplexofCatechinandS-Protein
during0–100nsofmoleculardynamicsimulation.
SupplementaryFiles
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Supplementaryinformation.pdf
... Indeed, these therapeutic approaches are supported by the SARS-CoV-2 similarity to other viruses from the same family that have infected people before; however, there is still no robust therapeutic evidence for COVID-19 [4]. In this context, some studies have demonstrated the potential of natural product-derived compounds, such as curcumin, against SARS-CoV-2 [8]. ...
... Such aspects will be further discussed. [8], Gonzalez-Paz, Lossada, Moncayo, Romero, Paz, Vera-Villalobos, Pérez, San-Blas and Alvarado [11]). Source: Own authorship. ...
... Furthermore, in view of the pursuit of new drug candidates for SARS-CoV-2 inhibition, in silico studies have demonstrated that curcumin has a dual inhibitory action at this target site: (i) inhibition of SARS-CoV-2-S (Fig. 1c) and (ii) inhibition of cell ACE II receptor [8]. Therefore, based on the role of ACE II on the SARS-CoV-2 replication cycle, curcumin emerges as a promising dual-inhibitor (directly and/or indirectly) of this target, which would disrupt the aforementioned viral pathway. ...
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The COVID-19 has become of striking interest since the number of deaths is constantly rising all over the globe, and the search for an efficient treatment is more urgent. In light of this worrisome scenario, this opinion review aimed to discuss the current knowledge about the potential role of curcumin and its nanostructured systems on the SARS-CoV-2 targets. From this perspective, this work demonstrated that curcumin urges as a potential antiviral key for the treatment of SARS-CoV-2 based on its relation to the infection pathways. Moreover, the use of curcumin-loaded nanocarriers for increasing its bioavailability and therapeutic efficiency was highlighted. Additionally, the potential of the nanostructured systems by themselves and their synergic action with curcumin on molecular targets for viral infections have been explored. Finally, a viewpoint of the studies that need to be carried out to implant curcumin as a treatment for COVID-19 was addressed.
... Plant secondary metabolites like lycorine [6], gingerol shogaol [7], resveratrol rhoifolin [8], oleanolic acid [9], kaempferol [10], rosmarinic acid [11], almond oil [12], ursolic acid [11], hederagenin, nigellidine, and α-hederin [11,13], apigenin, ethyl cholate, nobiletin, tangeretin, chalcone, and hesperidin [10,14,15], epigallocatechin gallate [16], allicin, diallyl trisulfide ajoene, and apigenin [14,17], aloenin [18], artemisinin [6,19], glucobrassicin [10,11], apigenin [11], curcumin [20], piperine [12], flavonoids, anthraquinone, and hydroxychloroquine [21], and jensenone [22] are reported to have antiviral activities. e mechanism of action of these secondary metabolites may be due to their greater binding affinity for SARS-CoV-2 6LU7 and 6Y2E proteases and inhibition of SARS-CoV-2 M protease (Mpro) and Spike (S) glycoprotein [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. ...
... Plant secondary metabolites like lycorine [6], gingerol shogaol [7], resveratrol rhoifolin [8], oleanolic acid [9], kaempferol [10], rosmarinic acid [11], almond oil [12], ursolic acid [11], hederagenin, nigellidine, and α-hederin [11,13], apigenin, ethyl cholate, nobiletin, tangeretin, chalcone, and hesperidin [10,14,15], epigallocatechin gallate [16], allicin, diallyl trisulfide ajoene, and apigenin [14,17], aloenin [18], artemisinin [6,19], glucobrassicin [10,11], apigenin [11], curcumin [20], piperine [12], flavonoids, anthraquinone, and hydroxychloroquine [21], and jensenone [22] are reported to have antiviral activities. e mechanism of action of these secondary metabolites may be due to their greater binding affinity for SARS-CoV-2 6LU7 and 6Y2E proteases and inhibition of SARS-CoV-2 M protease (Mpro) and Spike (S) glycoprotein [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. ...
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Background: Emerging viral infections are among the major global public health concerns. The pandemic COVID-19 is a contagious respiratory and vascular disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are no medicines that can treat SARS-CoV-2 except the vaccines. Therefore, searching for plant-originated therapeutics for the treatment of COVID-19 is required. Consequently, reviewing medicinal plants used to treat different viral infections is mandatory. This review article aims to review the ethnobotanical knowledge of medicinal plants traditionally used to treat different viral diseases by the Ethiopian people and suggests those plants as candidates to fight COVID-19. Methods: Articles written in English were searched from online public databases using searching terms like "Traditional Medicine," "Ethnobotanical study," "Active components," "Antiviral activities," and "Ethiopia." Ethnobotanical data were analyzed using the Excel statistical software program. Result: From the 46 articles reviewed, a total of 111 plant species were claimed to treat viral infections. Fifty-six (50.4%) of the plant species had reported to have antiviral active components that are promising to treat COVID-19. Lycorine, gingerol shogaol, resveratrol, rhoifolin, oleanolic acid, kaempferol, rosmarinic acid, almond oil, ursolic acid, hederagenin, nigellidine, α-hederin, apigenin, nobiletin, tangeretin, chalcone, hesperidin, epigallocatechin gallate, allicin, diallyl trisulfide, ajoene, aloenin, artemisinin, glucobrassicin, curcumin, piperine, flavonoids, anthraquinone, hydroxychloroquine, and jensenone were some of them. Conclusion: The Ethiopian traditional knowledge applies a lot of medicinal plants to treat different viral infections. Reports of the chemical components of many of them confirm that they can be promising to fight COVID-19.
... Also, Adem et al. (215) demonstrated that flavonoids may inhibit M pro used by SARS-CoV-2 for viral replication. Especially, quercetin and catechins have antiviral activity on SARS-CoV (216), and probably on SARS-CoV 2 (217,218). In addition, curcumin (219, 220) indomethacin and resveratrol have been proposed as potential supportive care supplements against COVID-19 (221). ...
... Vitamin C has an excellent safety profile, primarily due to its high water solubility and rapid clearance of excess levels by the kidneys (44,217). Although it is not possible to establish a UL for vitamin C, values of 1,000-2,000 mg/day have been suggested as prudent limits by some countries, based on a potential risk of osmotic diarrhea and related gastrointestinal distress in some individuals at higher doses (44,53). ...
... In another study using the technique of Molecular Docking, it was shown that curcumin has inhibiting effect on SARS-CoV-2 protease 3CL PRO which is comparable to conventional drugs like chloroquine and hydroxychloroquine (57). These findings are indicative of the potential herbal formulations that can be made using curcumin from C. longa in order to effectively combat SARS-CoV-2 (58). ...
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... Similarly, EGCG inhibits both HSV-1 and HSV-2 by binding to their envelope proteins such as gB, gD, or other envelope proteins, which help for the fusion of the virus to cells [96]. Catechin binds the receptor-binding domain of viral S-protein, as well as ACE2 of the host, thus may serve as a therapeutic agent for COVID-19 [97]. In one of the docking analysis study, compound EGCG found in green tea revealed the highest binding affinity with S protein of SARS-CoV-2, which reflects its potential usage in preventing or treating the COVID-19 patients. ...
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Ari Helenius launched the field of enveloped virus fusion in endosomes with a seminal paper in the Journal of Cell Biology in 1980. In the intervening years a great deal has been learned about the structures and mechanisms of viral membrane fusion proteins as well as about the endosomes in which different enveloped viruses fuse and the endosomal cues that trigger fusion. We now recognize three classes of viral membrane fusion proteins based on structural criteria and four mechanisms of fusion triggering. After reviewing general features of viral membrane fusion proteins and viral fusion in endosomes, we delve into three characterized mechanisms for viral fusion triggering in endosomes: by low pH, by receptor binding plus low pH, and by receptor binding plus the action of a protease. We end with a discussion of viruses that may employ novel endosomal fusion triggering mechanisms. A key take home message is that enveloped viruses that enter cells by fusing in endosomes traverse the endocytic pathway until they reach an endosome that has all of the environmental conditions (pH, proteases, ions, intracellular receptors, and lipid composition) to (if needed) prime and (in all cases) trigger the fusion protein and to support membrane fusion.
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(-)-Epigallocatechin-3-gallate (EGCG), one of the major flavonoid components of green tea, is known to have a broad antiviral activity against several enveloped viruses, including the influenza virus. However, its mode of action and the mechanism that allows it to target influenza virus molecules have not been fully elucidated. Thus, this study investigated the molecular mechanism by which EGCG suppresses influenza virus infections. EGCG was found to block an early step in the influenza viral life cycle, but it did not affect viral adsorption to target cells or viral RNA replication. However, EGCG inhibited hemifusion events between virus particles and the cellular membrane by reducing the viral membrane integrity, thereby resulting in the loss of the cell penetration capacity of the influenza virus. EGCG also marginally suppressed the viral and nonviral neuraminidase (NA) activity in an enzyme-based assay system. In conclusion, it is suggested that the anti-influenza viral efficacy of EGCG is attributable to damage to the physical properties of the viral envelope and partial inhibition of the NA surface glycoprotein. These results may facilitate future investigations of the antiviral activity of EGCG against other enveloped viruses as well as influenza virus.
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Consumption of green tea (Camellia sinensis) has been shown to cause many physiological and pharmacological health benefits. In the past two decades several studies reported that epigallocatechin-3-gallate (EGCG), the main constituent of green tea, has anti-infective properties. Antiviral activities of EGCG with different modes of action were described for viruses from diverse families like Retroviridae, Orthomyxoviridae and Flaviviridae and including important human pathogens like human immunodeficiency virus, influenza A virus and the hepatitis C virus. Furthermore, the molecule interferes with the replication cycle of DNA viruses like hepatitis B virus, herpes simplex virus and adenovirus. Most of these reports demonstrated antiviral properties within physiological concentrations of EGCG in vitro. In contrast, the minimum inhibitory concentrations against bacteria were 10 to 100 fold higher. Nevertheless, antibacterial effects of EGCG alone and in combination with different antibiotics were intensively analyzed against a number of bacteria including multidrug-resistant strains like methicillin-resistant Staphylococcus aureus or Stenotrophomonas maltophilia. Furthermore, the catechin EGCG has antifungal activity against human pathogenic yeasts like Candida albicans. Although the mechanistic effects of EGCG are not fully understood, there are hints indicating EGCG binds to lipid membranes and has influence on the folic acid metabolism of bacteria and fungi by inhibiting the cytoplasmic enzyme dihydrofolate reductase. This review summarizes the current knowledge and future perspectives about the antibacterial, antifungal and antiviral effects of the green tea substance EGCG.