THPdb: Database of FDA-approved peptide and protein therapeutics

12 Pages·2017·7.04 MB·English

RESEARCHARTICLE
THPdb: Database of FDA-approved peptide
and protein therapeutics
SalmanSadullahUsmani☯,GursimranBedi☯,JesseS.Samuel☯,SandeepSingh,
SouravKalra,PawanKumar,AnjumanAroraAhuja,MeenuSharma,AnkurGautam*,
GajendraP.S.Raghava¤*
BioinformaticsCentre,CSIR-InstituteofMicrobialTechnology,Chandigarh,India
☯Theseauthorscontributedequallytothiswork.
¤ Currentaddress:CentreforComputationalBiology,IndraprasthaInstituteofInformationTechnology(IIIT)
a1111111111
OkhlaPhaseIII,NewDelhi,India
a1111111111 *[email protected],[email protected](GPSR);[email protected](AG)
a1111111111
a1111111111
a1111111111 Abstract
THPdb(http://crdd.osdd.net/raghava/thpdb/)isamanuallycuratedrepositoryofFoodand
DrugAdministration(FDA)approvedtherapeuticpeptidesandproteins.Theinformationin
THPdbhasbeencompiledfrom985researchpublications,70patentsandotherresources
OPENACCESS
likeDrugBank.Thecurrentversionofthedatabaseholdsatotalof852entries,providing
Citation:UsmaniSS,BediG,SamuelJS,SinghS,
KalraS,KumarP,etal.(2017)THPdb:Databaseof comprehensiveinformationon239US-FDAapprovedtherapeuticpeptidesandproteins
FDA-approvedpeptideandproteintherapeutics. andtheir380drugvariants.Theinformationoneachpeptideandproteinincludestheir
PLoSONE12(7):e0181748.https://doi.org/
sequences,chemicalproperties,composition,diseasearea,modeofactivity,physical
10.1371/journal.pone.0181748
appearance,categoryorpharmacologicalclass,pharmacodynamics,routeofadministra-
Editor:Qing-XiangAmySang,FloridaState
tion,toxicity,targetofactivity,etc.Inaddition,wehaveannotatedthestructureofmostof
University,UNITEDSTATES
theproteinandpeptides.Anumberofuser-friendlytoolshavebeenintegratedtofacilitate
Received:December7,2016
easybrowsinganddataanalysis.Toassistscientificcommunity,awebinterfaceandmobile
Accepted:July6,2017 Apphavealsobeendeveloped.
Published:July31,2017
Copyright:©2017Usmanietal.Thisisanopen
accessarticledistributedunderthetermsofthe
CreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,and
Introduction
reproductioninanymedium,providedtheoriginal
authorandsourcearecredited. Withthesignificantadvancementsinbiologicsandbiopharmaceuticalovertheyears,peptides
andproteinshaveemergedwithahostofnewapplicationsinthediagnosticaswellasthether-
DataAvailabilityStatement:Wehaveuploadthis
datasettoastable,publicdatarepository"figshare" apeuticsector[1,2].Asperthecurrentcalculations,themarketforpeptideandproteindrugs
whichcouldbeaccessedatfollowingURL:https:// isestimatedaround10%oftheentirepharmaceuticalmarketandwillmakeupanevenlarger
figshare.com/articles/THPdb_Database_of_FDA_ proportionofthemarketinthefuture[3,4].Sinceearly1980s,atotal239therapeuticproteins
Approved_Peptide_and_Protein_Therapeutics/
andpeptidesareapprovedforclinicalusebyUS-FDA[5].
5198005.
Sincetheintroductionoffirstrecombinantproteintherapeutic,humaninsulin[6],proteins
Funding:Authorsarethankfultofundingagencies, haveemergedasamajornewclassoftherapeuticswithnearly380-marketedpharmaceutical
CouncilofScientificandIndustrialResearch(CSIR)
products.Proteinsastherapeuticshavedrawnalotofscientificattentionbecausetheyarepart
(projectOpenSourceDrugdiscoveryandGENESIS
ofmanyreceptorsandchannelsinthemembranes,whichfacilitatetransportofmolecules
BSC0121),andDepartmentofBiotechnology
withinthebody[7].Despitetheirinvolvementinvariousbiochemicalreactions,proteinsalso
(projectBTISNET),Govt.ofIndiaforfinancial
supportandfellowships. elicithighspecificitywiththemoleculartarget[7].Ontheotherhand,peptideshavealsobeen
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THPdb:DatabaseofFDA-approvedpeptideandproteintherapeutics
Competinginterests:Theauthorshavedeclared usedwidelyastherapeuticsincancer,diabetes,infectiousdiseasesandmanyotherdisorders
thatnocompetinginterestsexist. thathavelongbeenstudiedforasolution[8,9].Anadvantageofpeptidesoverotherdrugsis
thattheyarehighlyversatile,providingawidevarietyofpharmaceuticaltargets,highspecific-
ityandshowlowtoxicitylevels[5,9].Atotal60peptide-baseddrugsarealreadyinthemarket
andseveralothertherapeuticpeptidesarecurrentlybeingevaluatedindifferentphasesofclini-
caltrials[5].
Despitetheseveraladvantages,thereareafewdrawbacksassociatedwiththeseproteinand
peptide-basedtherapeutics.Limitationslikelowsolubility,proteolyticdegradation,relatively
shortcirculatinghalf-life,physiochemicalinstabilityandimmunogenicityrestricttheireaseof
administrationandcomplianceattheuserend[1,4,10].Theygenerallyhavehighmolecular
weights,lowlipophilicityandpresenceofsomechargedfunctionalgroups,whichtendtoham-
pertheirabsorptionatvarioussitesofthegastro-intestinaltract(GIT),resultingintheirlow
bioavailability[4].Severalstrategieslikeglycosylation,PEGylation,manipulationofamino
acidsequence,conjugationtoserumalbuminhaveemergedinordertoimprovethepharma-
cokineticandpharmacodynamicspropertiesaswellastodecreasetheimmunogenicityand
proteolyticcleavage[1,5].Withtheadventofnewtechnologies,incorporationofnon-natural
aminoacidsandpseudopeptidebondsalsoprovidewiderchemicaldiversitywithdiversified
potentialsandmakingiteconomicallymoreviable[4,11].
Overthelastdecade,aplethoraofdatabasesencompassinginformationonproteinand
peptideswithdifferenttherapeuticfunctionalities[12–19]havebeendeveloped,reflectingthe
increasedinterestforproteinsandpeptidesastherapeuticsamongthescientificcommunity.A
substantialinteresthasalsobeenshowntowardspeptide-basedsubunitvaccineandimmuno-
therapeutic[20].TheinformationonUS-FDAapprovedproteinandpeptidetherapeutics
alongwiththeirpharmacokinetic/pharmacodynamicproperties,theiradvantages,chemical
modifications,andtheirlimitationsareveryimportant.However,thisinformationisnoteasily
accessibleanditisscatteredintheliterature.Tothebestofauthors’knowledge,todate,nosin-
glefreelyavailableplatformexistswhichistotallydedicatedtoUS-FDAapprovedproteinand
peptidetherapeutics.Therefore,keepingtheabovefactsinmind,wehavedevelopedTHPdb,
whichisacomprehensiveresourceofallUS-FDAapprovedproteinandpeptidetherapeutics
alongwiththeircorrespondingdrugvariantsavailableinthemarket.Weanticipatethatthe
informationavailableintheTHPdbwillcertainlybeveryhelpfultotheresearchersworkingin
thefieldofpeptideandprotein-baseddrugdiscovery.
Methodsandmaterials
Datacollectionandcompilation
InordertocollectandcompilethelatestinformationonUS-FDAapprovedproteinandpep-
tidetherapeutics;first,wesearchedDrugBank[21]usingkeyword“biotechdrugs”with
“Approved”and“Investigational”filters.Thissearchresultedinto369biotechnology-based
drugson20thApr2017.Amongthese,only239werepeptidesandproteins,whichweresubse-
quentlyshortlistedforinclusionintheTHPdb.Further,inordertoprovidethecompletepro-
fileandcomprehensiveinformation(regardingthemechanismofaction,physicalform,route
ofadministration,categoryofactivity,interactionwithotherdrugs,recommendeddosages,
contraindications,sideeffectsandtheexploredtherapeuticareaoftheseshortlistedpeptides
andproteins),specificsearcheswerecarriedoutinthePubMedandpatentdatabasesusing
strings‘therapeuticproteins’,‘therapeuticpeptides’,andusingthenameoftheindividualpro-
teinandpeptide.Thesesearchesresultedintoatotal985publicationsand70patents.The
relevantinformationundervariousheadswascollectedandcompiledmanuallyfromthese
articles.
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THPdb:DatabaseofFDA-approvedpeptideandproteintherapeutics
Inordertoimprovethepharmacokineticparameterslikethevolumeofdistribution(Vd),
clearance(CL),orthebioavailability(AUC),differentmodificationsarebeingmadetothe
existingdrugmolecules(drugvariants).Here,inTHPdb,eachsuchmodificationwiththeir
brandnamescompiledinaseparateentry.Therefore,multipleentrieshavebeenmadeifa
drugmoleculehasbeenmodifiedindifferentwaysoritisbeingsoldunderdifferentBrand
names.Finally,atotal380drugvariantsofthesepeptidesandproteinshavebeensystemati-
callycompiledinTHPdb.
Databasearchitectureandwebinterface
THPdbdatabasehasbeenbuiltusingastandardplatformbasedontheLinux-Apache-
MySQL-PHP(LAMP).RedHatLinux(version6.2)astheoperatingsystem,MySQL(version
14.12)formanagingthedataandApache(version2.2.17)astheHTTPserverwasusedfor
developingthisdatabase.HTML5,PHP,JAVAscriptshavebeenusedfordevelopingthe
mobileandtabletcompatiblefrontendsandMySQLfordevelopingthebackend.Forthe
entiredatabaseinterfaceandthecommongateway,networksPHPandPERLcodinghave
beenused.ThearchitectureofTHPdbdatabaseisgiveninFig1.
Organizationofdata
Primaryinformation. Informationonproteinandpeptidetherapeuticswereobtained
manuallyfromdifferentresourcesandstoredasprimaryinformation.Eachentryincludesthe
followinginformation:nameofthetherapeuticmolecule,aminoacidsequenceorprimary
structure,molecularweight,chemicalformula,half-life,meltingpoint,hydrophobicity,iso-
electricpoint,toxicity,metabolism,pharmacodynamics,mechanismofaction,toxicity,indica-
tion/disease,metabolism,absorption,Vd,CL,categories,patentno.’s,dateofissueanddateof
expiryofthepatent,druginteractionsandthetargets.Inaddition,informationofcompany
name,brandname,formulation,recommendeddosage,sideeffects,contraindications,and
therouteofadministrationhavealsobeencollectedandstoredastheprimarydata.
Fig1.SchematicrepresentationofTHPdbarchitecture.
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THPdb:DatabaseofFDA-approvedpeptideandproteintherapeutics
Derivedinformation. Apartfromtheprimaryinformation,informationrelatedtofunc-
tion/activityofthepeptidesandproteinshavealsobeencompiled.Basedontheroleormode
ofactivity,therapeuticpeptidesandproteinsareclassifiedintofourgroups[7],GroupIconsist
oftheproteinswithenzymaticorregulatoryactivity,GroupIIofthosewithspecifictargeting
activity,GroupIIIareproteinvaccines,andGroupIVconsistsofdiagnosticagents.Thepro-
teinswithenzymaticorregulatoryactivityarefurthersub-dividedintothreecategories:(Ia)
thosereplacingadeficientorabnormalprotein,(Ib)thoseaugmentinganexistingpathway,
and(Ic)thoseprovidinganovelfunctionoractivity.Therapeuticswithspecifictargetingactiv-
itybeingsub-dividedintotwocategories:(IIa)peptidesinterferingwithamoleculeororgan-
ism,and(IIb)peptidesdeliveringothercompoundsorproteins.Similarly,groupIIIcontains
proteinvaccines,whicharesub-classifiedas(IIIa)vaccines,whichprotectagainstadeleterious
foreignagent,(IIIb)whichtreatsautoimmunediseasesand(IIIc)treatscancer.Thelastcate-
gorycorrespondstoproteinsthatcanbeusedasdiagnosticagents.Thisclassificationscheme
isexplainedpreviously[7].Thisinformationhasbeenstoredassecondarydata(Fig2).
Tounderstandthenatureofthesetherapeuticpeptidesandproteins,itisnecessaryto
understandtheirphysicochemicalproperties,whichhasbeencalculatedbyin-housePERL
scriptsthatwereusedtocomputeaminoacidcompositionandfrequencies.Alltheseproper-
tiesarehelpfulinanalyzingthetrendsanddeterminingtheaminoacidsdominatinginsuch
proteinsandpeptides.Thisphysiochemicalpropertybasedinformationisalsostoredassec-
ondarydatainthedatabaseforbrowsingofpeptides.
Manypropertiesexhibitedbythetherapeuticpeptidesandproteinsareduetotheirstruc-
turalcharacteristics.Thus,itisimportanttounderstandtherelationbetweenthestructuresof
thebiomoleculesanditsfunction.Wehavethusprovidedthestructuralannotationofeach
proteinandpeptideinourdatabaseusingthefollowingapproaches.Thestructuralinforma-
tionwasfirstextractedfromtheDrugBankusingtheProteinDataBank(PDB)entries[22](if
present)givenintheDrugBankfollowedbydownloadingitfromPDB.Incases,whereno
structuralinformationwasavailableineitherDrugBankorPDB,weusedbioinformaticstools
Fig2.Overviewofthefunction/modeofactivitybasedclassificationoftherapeuticproteinsand
peptides.
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THPdb:DatabaseofFDA-approvedpeptideandproteintherapeutics
forstructureprediction.I-TASSERsoftware[23]wasusedforpredictingstructureofproteins
havingmorethan30aminoacids.Incase,lengthofapeptideis30orless,thenPEPstrMOD
[2],whichisupdatedversionofPEPstr[24],hasbeenused.Ifaproteinorpeptidehasany
modifiedresidue(e.g.non-naturalresiduesandcappingofterminalresidues),itwaspredicted
usingPEPstrMODcontainingspecialforcefieldlibrariestohandlemodifiedresidues.
Implementationoftools
Dataretrievalorsearchtools. ThismoduleofTHPdbhasbeendesignedtofacilitate
searchingthedatausingsimpleandadvancedsearchoptions.Insimplesearchmodule,the
usercansubmitthequeryagainstanyfieldofthedatabasesuchasname,sequence,category,
classificationbasedontheirrole/modeofactivity,isoelectricpoint,indicationetc.Thisoption
resultsintoacustomizedoutputaccordingtothesearchquery.Intheadvancedsearchmod-
ule,theusercansubmitmultiplequeriessimultaneouslywithBooleanexpressions(eg.AND,
ORandNOT).Alongwiththesetoolsanddata,wehaveincludedauniquefeatureinourdata-
base,whicharethedownloadableself-explanatorypower-pointpresentations.Thesepresenta-
tionsarefreelyavailableandcanbedownloaded.Theusercanusetheseforacademicand
researchpurposes.
Browsing. Auser-friendlybrowsinginterfacehasbeendevelopedtofacilitateeasy
retrievaloftheinformationfromTHPdb.Wehavestoredphysicochemicalpropertiesofeach
therapeuticpeptideandproteinsuchasthehydrophobicity,isoelectricpoint,meltingpoint,
molecularweightandhalf-life.Userscanbrowsepeptideandproteinentriesforthedesired
physicochemicalproperties.
ToaccessthedatainTHPdb,variouscross-linkedbrowsabletableshavebeenprovided.
Theuserscanbrowseonsevenmajorfields:(i)diseaseareaofactivity,(ii)numberofamino
acidsintheproteinorpeptide,(iii)classificationbasedontheirfunction/modeofactivity,(iv)
physicalappearancestate(v)routeofadministration(vi)category/pharmacologicalclassand
(vii)targetbasedclassification.
Sequencealignment. Inordertofacilitatesequencesimilaritybasedsearch,wehaveinte-
gratedBLASTandSmith-Watermanalgorithm.Userscansubmittheirproteinorpeptidein
FASTAformatwithdefaultordesiredparametersofBLAST[25].TheserverperformsBLAST
searchfortheuser’squerysequenceagainsttheaminoacidsequencesortheprimarystruc-
turesofallthepeptidesandproteinsinthedatabase.Similarly,Smith–Watermanalgorithm
[26]hasalsobeenintegrated.Inadditiontoabovesimilaritysearchfacility,theserveralso
allowssequencemappingbasedonidenticalresidues.Sub-searchandsuper-searchhavebeen
integratedastwomappingoptions.Byusingsub-searchmodule,usercanmapquerypeptide
againstallthepeptidesandproteinsenteredinTHPdb,whereassuper-searchallowsmapping
oftheproteinsequenceagainstTHPdbandidentificationofsegmentsthatareidenticalto
therapeuticpeptides.
MobileApp
Toassistthemobileusers,wehavedevlopedamobileApp.THPdb(mobileapp)isacompre-
hensivedatabaseapplicationofUS-FDAapprovedpeptideandproteintherapeuticsdeveloped
tofacilitateitssmoothusageonmobileplatforms.ThecurrentmobileversionofTHPdbcom-
patiblewithandroidmobilesexploitspython(v2.7.11)andkivy(v1.9.2).TheApplistsvarious
diseasetypesandadropdownmenuofpotentialtherapeuticpeptidesfollowedbydetailed
informationofdrugsforindividualproteinandpeptide.Theimportantinformationforindi-
vidualentityhasbeensortedintoindividualpanelscalled“peptide-card”whichcanbeeasily
downloaded.Eachpeptide-cardfeatures/hostsinformationaboutthepeptide/protein
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Fig3.TheflowdiagramexplainstheworkanddesignofTHPdbmobileapplication.
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therapeutics,theirdescription,sequence,indication,pharmacodynamics,mechanismof
action,ADMEinformation,toxicologicalinformation,metabolism,absorption,halflife,clear-
ancerate,patentinformation,drug-druginteractions,potentialtargets,physicochemicalprop-
ertiestonameafew.The‘THPdb’mobileapplicationisprovidedinstandard“.apk”file
formatwhichcanbedownloadedfromhttp://crdd.osdd.net/raghava/thpdb/mobile.php
Appworkingoutline. THPdbappisdividedintovariouslevelstoprovideaninteractive
outlineofthedatabase.AsshowninFig3,databaseexplorationbeginswiththeselectionofa
diseasetypefromthe“Browse”tab.Inthenextlevel,apeptideofinterestissearchedamong
thelistofUS-FDAapprovedpeptideandproteintherapeuticsfortheselecteddiseasesto
obtainalistofpotentiallyapproveddrug(s).Thehitsharesahandfulofinformationlikedrug
brands,theirmanufacturers,androuteofadministrationofcorrespondingtherapeuticpeptide
/protein.Morecomprehensiveinformationofimportantfieldscanberetrievedbydownload-
ingthe“PeptideCard”thatisavailableatthebottomoftheeachpeptidepage.
Results
THPdbdatastatistics
ThecurrentversionofTHPdbholdsatotalof852entriesprovidinginformationon239
US-FDAapprovedpeptideandproteindrugsandtheir380drugvariants.Corresponding
drugvariantsoftherapeuticproteinsandpeptideswereclassifiedonthebasisofaclassification
presentedbyLeaderetal.Ofthe380drugvariants,229involvedinregulatoryandenzymatic
activityfollowedby78belongingtothetherapeuticswithspecialtargetingactivity.Atotalof
58drugvariantsbelongtothevaccinescategoryand15tothediagnosticagents.
Inaddition,thesedrugvariantshavealsobeengroupedonthebasisofdiseaseinwhich
theyarebeingusedfortherapy.Atotalof89drugvariantsshowactivityincaseofmetabolic
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Fig4.Aschematicrepresentationofdistributionoftherapeuticpeptidesandproteinsbasedon
disease,function/modeofactivity,routeofadministration,andpharmacologicalclass.
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disorders,80haveactivityintheimmunologicaldiseasearea,74forhematologicaldiseases,61
inthecancertherapy,63inhormonaldisorders,46variantsusefulforgeneticdisorders,35in
infectiousdisease,14incardiovasculardisorders,10havethepotentialtocurebonedisorders,
07usedinneurologicaldisorder,06forrespiratorydisorder,05variantsaregivenasadjunct,
03ineyedisorder,and01varianthasbeenusedinmalabsorptiondisorder.
Theroutesbywhichthesevariantsarebeingdeliveredhavealsobeencompiledsystemati-
cally.Total158drugsbyintravenousinfusions,116drugvariantsaredeliveredbysubcutane-
ousinjections,49drugsbyintramuscularroute,13drugsviatheoralroute,4byintra-vitreal,
2byintralesional,2byintratracheal,1byintracoronary,and3drugvariantsarebeingused
externallyasointments.AllthesedatastatisticshavebeensummarizedinFig4.
Inordertoassistusers,wehaveprovidedpower-pointpresentationscontainingdetailed
informationofeachUS-FDAapprovedproteinandpeptidetherapeuticincludingtheir
sequenceorprimarystructure,molecularweight,chemicalformula,description,indication,
pharmacodynamics,mechanismofactionanditsinteractionwithotherdrugs.Thesepresenta-
tionscanbedownloadedfromtheTHPdbwebsite.
Comparisonwithexistingresources
Despitethefactthatpeptidesandproteinsaregainingtremendousscientificattentionasthera-
peuticsnowadays,nosinglerepositoryexiststilldatewhichcanprovidecomprehensiveinfor-
mationonallUS-FDAapprovedproteinandpeptidetherapeutics.However,twodatabases,
ChEMBL[27]andDrugBankprovidetheinformationonUSFDAapprovedproteinandpep-
tidetherapeuticstoacertainextentbuttheydon’tcoveralltheUS-FDAapprovedproteinand
peptidetherapeuticsandtheirdrugvariants.Asof1stMay2017,ChEMBLprovidesinforma-
tionofonly191proteinandpeptidetherapeuticsandinformationof48proteinandpeptide
therapeuticsismissing.Inaddition,amongthese191proteinandpeptidetherapeutics,
ChEMBL,providesstructuralinformationofonly148proteinandpeptidetherapeutics.Simi-
larly,incaseofdrugvariants,ChEMBLprovidesinformationof144variantsonly.DrugBank
storesomeinformationaboutproteinandpeptidetherapeutics,butitdoesn’tgivedetailed
descriptionofcorrespondingdrugvariantsofthesepeptideandproteintherapeutics.Inaddi-
tion,DrugBankprovidesPDBIDofonly107proteinandpeptidetherapeutics,whereas
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THPdb:DatabaseofFDA-approvedpeptideandproteintherapeutics
THPdbprovidestructuralinformationofabout156proteinandpeptidetherapeutics.Inorder
toovercomethelimitationsoftheaboveresources,wehaveincorporateddetailedinformation
ofall239proteinandpeptidetherapeuticsandtheir380variants.Besidesthis,comprehensive
information(theirsequence,physico-chemicalproperties,structure,pharmacokinetics,phar-
macodynamicsproperties,etc)ofeachproteinandpeptidetherapeuticandtheirdrugvariant
wasprovidedintheformofpower-pointpresentations.Usercanfreelydownloadthepower-
pointpresentations.Thus,THPdbprovidesthelatestandcomprehensiveinformationandisa
complementaryresourcetotheexistingdatabases.
Discussion
Smallpeptidesandproteinswereneverconsideredastheidealtherapeuticmolecules,however,
overthelastfewdecades,arevivalofinterestinpeptideandproteintherapeuticshasbeenseen
amongthepharmaceuticalandbiotechindustries[1].Thiscanbeevidencedbytheincreasing
rateofpeptidesandproteinsentryperyearintheclinicaltrials[9].In2012alone,sixpeptides
wereapprovedasdrugsbyUS-FDA[11].Despitetheimmensepopularityofproteinsandpep-
tidesastherapeutics,theinformationofallalreadyUS-FDAapprovedproteinandpeptidether-
apeuticsisfarfromreach.Therefore,inthepresentstudy,anattempthasbeenmadetoprovide
acomprehensiveinsightontheUS-FDAapprovedpeptideandproteintherapeuticsincluding
alltheinformationontheirphysical,chemicalandactivityrelatedcharacteristics.InTHPdb,all
thisinformationhasbeencompiledinasystematicmanner,whichwillhelptheresearchersto
lookintoavarietyofaspectsofaparticularproteinorpeptidesimultaneously.
Developmentofadrugisacomplexandtime-consumingprocess.Eventhoughpeptides/
proteinsarehighlyactiveintheirnativeform,theyneedtobemodifiedinseveralwaysin
ordertobecomeadrugmolecule.Theseseriesofchangesmaketheleadmoleculeasabetter
therapeuticcandidateandthepriorknowledgeofsuchchangesormodificationswillbevery
usefulindevelopingfuturedrugs.Thepeptideresearchersmaybeinterestedtoknowthehalf-
life,chemicalmodifications,immunogenicity,solubility,sideeffects,toxicity,pharmacody-
namics,differentformulations,dosageforms,andthedifferentbrandnamesunderwhich
thesedrugsarecurrentlysoldinthemarket.Inthiscontext,THPdbisveryhelpfulinthe
developmentofnoveltherapeuticentities,particularlyduringtheinitialphasesofdrugdiscov-
erybyunderstandinghowthedrawbackshavebeenovercomeinUS-FDAapprovedpeptide
andproteintherapeutics.Forexample,thevariousmodificationsmadetoimprovethethera-
peuticprofilesofUS-FDAapprovedproteinswillgiveresearchersmanycluestoimprovethe
therapeuticprofileoftheirleadmolecules.
Utilityofdatabase
OneofthemajoradvantagesofTHPdbisthatuserscangetthecompleteinformationon
US-FDAapprovedproteinandpeptidetherapeutics,whichwasnotpreviouslyavailableona
singleplatform.THPdbprovidesitsuserswithnumerousservices,like(i)userscancheck
whethertheirpeptidesorproteinsofinteresthasalreadybeenreportedornot,andhowdiffer-
entorsimilartheirproteinorpeptideiswiththeexistingapprovedtherapeutics,(ii)whatkind
ofmodificationshasbeendonetoincreasetherapeuticcompetencyofthetherapeuticslike
half-life,rateofclearance,etc.,and(iii)userscanexploitthestructuralinformationofthese
peptidesprovidedinTHPdbformoleculardynamicsordockingstudies.Inaddition,amobile
applicationisalsodevelopedwiththeaimofmakingiteasyfortheresearchers.
Besidesthis,THPdbalsoprovidesself-explanatoryresourceinpower-pointformat,which
willbeveryhelpfulforacademicians,andresearchersandwehopethatitwillaccomplishour
mainaimbehindthisdatabasei.e“academicenhancement”and“knowledgeenrichment”.
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Fig5.RepresentativescreenshotsofTHPdbdemonstratingtheflowofinformationaftersubmissionofaqueryinsimplesearchpage.
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Casestudy:Howtoretrieveinformationabout“Insulin”fromTHPdb. Herewehave
shownstep-by-stepaboutwhatkindofinformationausercanfetchfromTHPdb.Wehave
useInsulinastherapeuticsinacasestudytoexplainthis.Belowisthedescription:
Ifuserwantstoknowaboutthedifferenttypeofinsulindrugs(drugvariants)approved
byUS-FDA,userhastotypeInsulininthespaceprovidedinthesimplesearchoption(Fig
5A)oralternativelyusercanuseadvancesearchtoolaswell.Onsimplesearchpage,anumber
offieldsareprovidedonwhichusercanfetchtheinformation.Atatime,usercanselecta
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THPdb:DatabaseofFDA-approvedpeptideandproteintherapeutics
maximumof7fieldstobedisplayed.Afterselectingfields,userhastosubmitthequeryand
searchwillendupwithallinsulin-baseddrugsanditsvariantsavailableinthemarketunder
differentbrandnames.Forexample,here,atotal52entriescomprising17insulindrugsand
itsvariantsaredisplayedalongwithinformationonselectedfields(Fig5B).Usercanalsoclick
onindividualentryIDinordertoobtainthedetailedinformationforaparticularinsulindrug
asshowninFig5C.Bydoingso,usercangettheallpossibleinformationofthatparticular
druglikesequence,physico-chemicalproperties,pharmacokineticsandpharmacodynamics,
half-life,side-effects,routeofadministration,dosageform,brandname,etc.Inaddition,user
canalsogetthestructuralinformationbyclickingon3-Dstructureoptionprovidedinthe
detailedinformationpageFig5D.
Limitationsanddatabaseupdate
Whilecompilingthedataundervariouscategoriesforeachpeptideandprotein,wefaced
somechallenges,asthesequenceof57oftheapprovedpeptidesandproteinscouldnotbe
obtainedfromanyoftheavailablesources.Thesearemainlythemonoclonalantibodiesanda
fewpeptideantibiotics.Thisinformationwillbeupdatedinthedatabaseassoonasthenew
informationisavailableintheliterature.
Acknowledgments
Authorsarethankfultofundingagencies,CouncilofScientificandIndustrialResearch(CSIR)
(projectOpenSourceDrugdiscoveryandGENESISBSC0121),andDepartmentofBiotech-
nology(projectBTISNET),Govt.ofIndiaforfinancialsupportandfellowships.
AuthorContributions
Conceptualization:GPSR.
Datacuration:SSUGBJSSSKAAA.
Formalanalysis:SSUSSPKMS.
Investigation:SSUGBJSSSKAAA.
Methodology:SSUSS.
Projectadministration:GPSR.
Resources:GPSR.
Software:SSUSSPKMS.
Supervision:GPSR.
Validation:GPSR.
Visualization:SSUAG.
Writing–originaldraft:SSUAG.
Writing–review&editing:SSUAGGPSR.
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