FutureProtein-LigandChallenges:CELPP&NewDatasets

VickiFeher

CELPPWeeklyautomatedcross-dockingchallengesenabledbyPDBreleaseofsmallmolecule&proteinsequencesWeenvisionthreepossiblewaystoparDcipate:

1.Dockingprogramhostedonourinternalserver2.Automatedlinkbetweenourwebservicesandanexternalautomated dockingwebsites3.Downloadingourweeklyposts&uploadingresults

CanwemovebeyondreproducingPDBstructureposes?

1.Workwiththejournals/PDBtohavenoDficaDonof“accepted”papers and“HOLD”structureswithaffiniDes.2.SGC-Torontowillprovide~1-2monthnoDceofdatasetsbeing preparedforpublicaDon

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CELPPStatus

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CELPPWeek

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Stage2:BLAST-n-FilterWorkflow

Queryfilter•  #ofuniquesequences•  #ofdockableligands

Read.tsvfiles•  Filterligands

-  Dockable?

BLAST

Hitfilter•  %idenDty(#idenDcal/#aligned)•  %coverage(#aligned/#query)•  #ofuniquesequences•  Experimentalmethod

Candidatefilter•  LargestMCSS•  SmallestMCSS•  HighestresoluDonapo•  HighestresoluDonholo

Writelog Writesummary Postanalysis•  Parselog•  XLSX•  Resname,PNG

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Numbersbyweek

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Complexes

Dockablecomplexes

Dockablemonomers

TargetsFound

Stage4:Docking•  Currentonourserver

–  OEDocking–  CCDC:GOLD–  Schrodinger:Glide–  AutoDock

•  Outreachto–  Shoichet,DOCK3.7–  RobertRizzoDock6.7–  Jain,Surflex

•  EvaluaDonswillbesameasthoseforGrandChallengesandautomatedintheCELPPworkflow;RMSD,RSR,ROCS(orsometypeofinteracDonfingerprint)

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Stage5:EvaluaDon

Feedback•  Ideasforhowbesttopostresults?

•  Whatsortofresultsshouldwepost?

•  WoulditbeusefultopostresultsrelaDvetousingvariousligandpreparaDonmethods?–  Ie.tautomerpredicDon,pKapredicDons

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NextChallenges

ITK–GenentechdonaDon

FXR–RochedonaDon

FBPase–RochedonaDon

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FarnesoidXreceptor(FXR)Roche

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AnuclearreceptorinvolvedincholesterolandbileacidhomeostasisAntagonistsarepotenDaldyslipidemialoweringagentsandpotenDalTypeIIdiabetestreatmentsThebindingsiteishighlylipophilicandflexible4disDnctchemotypes+6miscellaneouscompoundsThereare~25+publishedcrystalstructures,includingexamplesofthesechemotypecrystalstructurespublished

Fructose-1,6-bisphosphataseRoche

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Aproteininvolvedingluconeogenesis,convertsfructose-1,6-bisphosphatetofructose-2,6-bisphosphateTargetfordecreasingglucoseproducDonforTypeIIdiabetesAllostericallyregulated;thecompoundsaretargeDngtheallostericsite2chemotypes+somemiscellaneouscompoundsThereare~20+publishedcrystalstructures,includingexamplesofthesechemotypecrystalstructurespublished

D3RTeam

MikeGilson

MikeChiu

HuanwangYang JasmineYoung

JeffGrethe

RommieAmaro VickiFeherStephenBurley

SymonGathiaka ShuaiLiu JeffWagner

ChrisChuras

ThankstoPreviousDatasetDonors

•  Roche•  Genentech•  GSK•  Abbvie•  Vertex

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