Let’s develop together an exchange virtual compounds ... · 1st annual mee+ng of MuTaLig COST...

1stannualmee+ngofMuTaLigCOSTAc+onCA15135,Lugano22July2016

Let’sdeveloptogetheranexchangevirtualcompoundscomputa6onalpla7orm

Francesco Ortuso

University“MagnaGræcia”ofCatanzaroItaly


Some(trivial)data

Industrialresearch(aquasi-failurestory)

•  the11.8%ofunderdevelopmentdrugswillarrivetothemarket1

•  ~25-30newdrugs/year2

•  200-250candidates/newdrugfailsduetoADME-Toxreasons•  molecules/candidate=hundreds•  50K-75Kfailedcandidates/yearcorrespondingto500K-750Kdiscarded

molecules/year

Academicresearch(afull-failurestory)

•  morethan100,000scienWficpapers/yearinChemistryResearchfield(ISI)•  tensofcandidatedrugs/year•  anydrugonthemarket

1DiMasi,J.A.;Grabowski,H.G;Hansen,R.W.N.Engl.J.Med.2015,20,19722Kinch,M.S.;Haynesworth,A.;Kinch,S.L.;Hoyer,D.DrugDiscovToday.2014,19,1033-1039


Whataboutfailedcompounds?

PharmaceuWcalIndustries•  trydrug-repurposing•  publishsomescienWficpaper•  buildcommercialdatabases(tosoldfailedmolecules)•  forgetfailedmoleculesinstorageareas

UniversiWes•  completelyforgetfailedmolecules•  trydrug-repurposing,onlyrecentlyandinveryfewcases

AlotofmoleculesarewaiWngforus!


Somealreadyavailabledatabase

•  ZINC(zinc.docking.org)

•  ChEMBL(www.ebi.ac.uk/chembl)•  PubChem(pubchem.ncbi.nlm.nih.gov)•  NCI(dtp.cancer.gov)•  ChemSpider(www.chemspider.com)•  DrugBank(www.drugbank.ca)•  WOMBAT(dud.docking.org/wombat)•  DUD(dud.docking.org)•  CSD(www.ccdc.cam.ac.uk/soluWons/csd-system/components/csd)•  eMolecules(www.emolecules.com)•  ChemBank(chembank.broadinsWtute.org)•  GILDA(pharminfo.pharm.kyoto-u.ac.jp/services/glida)•  …....


DoesitmakesenseyetanotherDB?

•  availableDBscontainmillionofcompounds•  intermsofbothcomputaWonalandchemicalresources,availableDBsare

welldone•  theyallowtogetmolecules+some“informaWon”aboutthem•  itisveryhardtomakesomethingbeker,but….•  availableDBsare“closed”

–  Vendorsfurnishcompounds(virtuallyandmaterially)–  Researchersusecompounds(and,usually,buythemfromvendors)–  Anyfeedbackcomesbackfromnewtests(usually)–  AnycollaboraWonispromotedbetweenvendorsandresearchers(different

goals)–  AnycollaboraWonispromotedamongresearchers


WhatMu.Ta.LigChemothecacouldbe

•  Acommunitybased“open”DBbasedforscienWficdatasharing:–  Webaccessiblebothbyregisteredandguestusers(withdifferentlevelof

informaWonallowed).–  Registereduserswillbe:

a)  “SyntheWcs”,whosyntheWzedanduploadedthemolecule(i.e.WG1)b)  “Experimentals”,whoretrievedthemoleculeandtestedit(i.e.WG2)c)  “TheoreWcals”,whoretrievedthemoleculeanduseditformolecularmodelling

invesWgaWon(i.e.WG4)

–  “SyntheWcs”canuploadtheirownmoleculesanddecidethepolicytoaccessthem.

–  “Experimentals”interestedonacertainmolecule,willcontactthe“SyntheWcs”ownerandwilltakeaccordwithhimforobtainingthehit.

–  Chemothecawillrequireto“Experimentals”toupdateacWvityinformaWonrelatedtoretrievedcompounds.

–  “TheoreWcals”willhaveaccesstotheChemothecaandtheymakeacommitmenttoinserttheirtheoreWcalinformaWon.


Chemotheca’snetwork

DB

“Synthe6cs”

“Experimentals” “Theore6cals”

“Guest”Registra6on


HowChemothecaisandcouldbedeveloped

•  TheenWretoolis(andwillbe)basedonopen-sourceprogramminglanguagesandarchitectures:–  MulWprocessorLinuxcomputerservers–  Apachehkpdemon(ver.2.2)–  WebuserinterfacefrontendiswrikeninPHP(ver.5.1)–  Cookieswillbeadoptedforsessiondata–  DatabasebackendisMySQL(ver.5)–  JSME(orsimilar)moleculeeditorforsearchingandupdaWnguploaded

structures


What’sthedevelopmentstateofChemotheca?

Theminuswasdone!

• Homepage:done!• Logincode:todo• RegistraWon:50%done• News:todo• Contactus:todo• SearchUI:todo• UploadUI:50%done• UpdateUI:todo


Whatinforma6oncouldbeshowed

VisibletoGuestusers•  Molecularstructure(ifallowedbytheowner)

Visibletoregisteredusersonly

1.  Molecularstructureandownerdata2.  BiologicalinformaWon(i.e.alreadytestedtargetsandcorresponding

acWvity)3.  Physico-chemicalexperimentalinformaWon(i.e.MW,solubility,melWng

point)4.  TheoreWcaldescriptors(i.e.Lipinskirule,LogP,LogD,tautomers,

conformers)

Points2,3and4willindicate“who”insertedthedataand“when”ithasbeendone


Fewsharingrules

•  Whovirtuallyuploadamoleculewillbealwaysitsownerandhewillbefreetotakeaccordsforcompoundsdelivery.

•  Biological,physico-chemicalandtheoreWcaldatabecomepropertyofChemotheca’sregisteredusersBUTexperimental/computaWonaldetailsmustberequiredtothedataproducersandtheywillbefreetotakeaccordsforfurnishingsuchsupplementaryinformaWon.

Nobodywilllosetheintellectualpropertyonitsowndataand

somemoleculecouldliveasecondyouth!


Chemotheca’sespectedresultsandrequirements

•  ApotenWallylargenumberofavailablehighqualitycompoundswillbeclassified

•  EachcompoundwillincludeoneormoreacWvitydata:–  ImprovedknowledgerelatedtopolypharmacologyandpotenWalsecondary/

sideeffects•  ScienWficcollaboraWonamongChemotheca’suserswillbepromoted

Chemotheca’sgoalsarestrictlyrelatedtotheuserscontribute!


What’stheeasierwayforcontribu6ng

•  “SyntheWcs”:compoundsupload

•  “Experimentals”:compoundsacWviWesupdate

•  “TheoreWcals”:compoundsdescriptors,theoreWcalacWviWesupdate


Compoundsupload

•  MandatoryinformaWon:–  ID(decidedbytheownerforitseasiercompoundidenWficaWon)–  Molecularstructure(includingstereochemistry)–  Stereochemistry–  Isitasalt?y/n

•  OtherinformaWon(ifavailable):–  MelWngpoint(°C)–  Watersolubility(g/L)–  DMSOsolubility(g/L)–  Ethanolsolubility(g/L)

•  Uploadways–  Webform–  Spreadsheet(xlsx,odsorcsv)–  ….


Webform


Usingspreadsheet

•  onerow->onecompound•  1strowcontainscolumnlabels•  informaWonstartatrown.2•  ColumnA:compounduniqID(notblankspaceareallowed)•  ColumnB:compoundInChIkey•  ColumnC:compoundstructureasSMILEstring(becarefultothe

stereochemistry)•  ColumnD:isitsalt(y/n)•  Column>=E:otherinformaWon(ifavailable)


AXerspreadsheetuploadcheck

•  AtablereporWnguploadedinformaWonand2Dcompoundstructureswillappear

•  Pleaseverifythestereochemistryand,incaseoferror,willbepossibletoeditordeletetheentry

•  Ifthecompoundisasalt,don’tcareabouttheionsrelaWveposiWon

•  Wheneverythingsounds…..Goahead!

ThecodehastobewriKen…


Compoundsac6vitydataedi6ng

•  BymeansofsearchUI,registereduserswillselectmolecule(s)ofinterest

•  RegistereduserswillcanaddnewinformaWon(i.e.TargetIC50innM)–  Itwillbemandatorytospecify:(a)target,(b)kindofmeasurementand(c)

measureunit(i.e.nM)

•  AddedinformaWonwillbeavailableforallregisteredusersbutcanbeeditedbytheirowneronly

•  IfacertaincompoundwillbereWredbyitsowner,itwillremainintotheChemothecabutitwillmarkedas“unavailable”


Chemotheca’susage

•  UserswillbeallowedtosearchtheDBbymeansof:

–  Textualwebform(TWF),usingthecompoundproperWesandbooleanoperators•  CompoundID,InChIkey,Molecularweight,Lipinskirule(orotheravailabledescriptors),target,kindofacWvity(IC50,Ki,ED50)

–  Amoleculareditor(ME),usingexactorsubstructuresearchalgorithm

•  TWFandMEcouldbeusedtogetherinadvancedsearch

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Let’s develop together an exchange virtual compounds ... · 1st annual mee+ng of MuTaLig COST...

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