future protein-ligand challenges: celpp & new datasets · 2. automated link between our...
TRANSCRIPT
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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