new walters d3r 2018 - d3r | welcome... · 2018. 3. 5. · pat walters – d3r workshop february...
TRANSCRIPT
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Howcanwegetbetteratthis?
PatWalters– D3RWorkshopFebruary23,2018
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I’veDoneThisaFewTimes
2012 2013 2015 2016 2017 20182014
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3
HowISpendMyTimeOnChallenges
Confidential|©2017RelayTherapeutics
Dealingwithpoorlyformattedsubmissions
Validatingevaluations MakingSlides
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4
TheEvaluationProcess
Confidential|©2017RelayTherapeutics
PatEvaluate
ConnorandZiedEvaluate
FinalComparisons
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5
TheLiteratureMakesItLookLikeActivityPredictionisaSolvedProblem
Confidential|©2017RelayTherapeutics
0.82 0.80
0.66 0.65
Pearsonr
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6
ScoringPerformanceFromGC2andGC3
Confidential|©2017RelayTherapeutics
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
7
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
8
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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Whenevaluatingaregressionmodel,thedatasetshouldhaveadynamicrangesimilartothoseobservedindrugdiscoveryprojects(typically4-6logs)
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DatasetsShouldSpanaReasonableDynamicRange
Confidential|©2017RelayTherapeutics
Thisdataset(PDBindv.2016coreset)spans10logsanddoesn’tprovideanappropriaterepresentationofcorrelation
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CorrelationsCanChangeDramaticallyWithDynamicRange
Confidential|©2017RelayTherapeutics
R2=0.22MAE=0.69
R2=0.76MAE=0.55
Thisisthesamedataset.Ontheleftweconsidertheentireset,whichhasanunrealisticallylarge(~10log)dynamicrange.Ontherightweconsideramorerealisticsubsetwitha3logdynamicrange.Notethechangeincorrelation.
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GC3CatSDatasetSpansaRealisticDynamicRange
Confidential|©2017RelayTherapeutics
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
12
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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Don’tCramMultipleDatasetsontotheSamePlot
Confidential|©2017RelayTherapeutics
http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.7b07224 http://pubs.acs.org/doi/abs/10.1021/ja512751q
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EvenMyFriendsAreGuilty
Confidential|©2017RelayTherapeutics
MillandNeysa(Yesterday)
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Trellisingprovidesamuchmoreeffectivemeansofcomparingdatasets
Confidential|©2017RelayTherapeutics
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
16
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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ReportPearson,SpearmanandKendallcorrelationsFavorR2 overRwhenreportingaPearsoncorrelationcoefficientReportMAEand/orRMSE
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Alwaysreportcorrelationsappropriately
Confidential|©2017RelayTherapeutics
Ihavenoideawhatthismeans
http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.7b07224
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MaximumAchievableCorrelation
Confidential|©2017RelayTherapeutics
StartwithexperimentaldataAddGaussianerror
§ Mean=0.0§ Standarddeviation=0.3log
CalculationcorrelationRepeat1000times
Brown,ScottP.,StevenW.Muchmore,andPhilipJ.Hajduk."Healthyskepticism:assessingrealisticmodelperformance.”DrugDiscoveryToday14.7(2009):420-427.
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MaximumAchievableCorrelation- HPS90D3R1
Confidential|©2017RelayTherapeutics
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https://github.com/PatWalters/metk
OpenSourceEvaluationCode(MoretoCome)
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
21
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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EnsureThatDifferencesinCorrelationAreSignificant
Confidential|©2017RelayTherapeutics
Inparticular,bothMM-PB/SAandMM-GB/SAproducedbetterresultsbyusingarepresentativestructure(R)0.72-0.79)ratherthanaveragingovertheconformationalensembleofeachgivencomplex(R)0.61-0.74
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23Confidential|©2017RelayTherapeutics
M1_dynamic M1_static M2_static M3_dynamic M3_static M4_dynamic M4_static
Table L2
abs(
Pea
rson
r)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Aliteraturecomparisonof7methodsforscoringprotein-ligandinteractions
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Rememberthatcorrelationshaveconfidenceintervalsandreporttheseintervals
Confidential|©2017RelayTherapeutics
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It’sAlltheSame!
Confidential|©2017RelayTherapeutics
M1_dynamic M1_static M2_static M3_dynamic M3_static M4_dynamic M4_static
Table L2
ab
s(P
ea
rso
n r
)
0.0
0.2
0.4
0.6
0.8
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
26
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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MolecularweightandcalculatedLogParepoornullmodels
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GenerateRDKitfingerprintsforligandsTrainonPDBbindrefinedset(n=4057)TestonPDBbindcoreset(n=290)Wallclocktime<5min
28
SimpleQSARasaNullModel
Confidential|©2017RelayTherapeutics
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29
WhatConstitutesanAppropriateNullModel
Confidential|©2017RelayTherapeutics
MolecularWeight XLogP SimpleQSAR
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ANullModelforRMSE
Confidential|©2017RelayTherapeutics
1.SampleNobservedvalues2.CalculateRMS3.Repeat1and2*1000
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NullModelforGC1HSP90FreeEnergyChallenge
Confidential|©2017RelayTherapeutics
RMSE(kcal/m
ol)
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ComparingRMSvsNullforGC1HSP90Challenge
Confidential|©2017RelayTherapeutics
Dashedlineindicatesthenullmodel
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
33
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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Alwaysprovideamachinereadabletable(e.g.csv)ofpredictedandexperimentalvaluesAtableinapaperisnotsufficient,itisoftenverydifficulttoextracttablesfrompdffilesChemicalstructuresshouldbeincludedasSDFor,whereappropriate,SMILEStofacilitatecomparisonwithothermethodsNeedtoenablereaderstoevaluatecorrelationsanderrors
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Includeappropriatesupportinginformation
Confidential|©2017RelayTherapeutics
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
35
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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36
CanIReproduceYourMethod?
Confidential|©2017RelayTherapeutics
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Code!!!AthoroughdescriptionofyourmethodAwebimplementationNoneoftheabove
37
WhatConstitutesReproducibility?
Confidential|©2017RelayTherapeutics
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Weneedtoagreeon• Whatconstitutesareasonabledataset• Howdatashouldbereported• Evaluationmetrics• Statisticsforcomparison• Whatconstitutesanullmodel• Formatofsupportingmaterial• Criteriaforreproducibility
38
GuidelinesForReviewing”ScoringFunction”Papers
Confidential|©2017RelayTherapeutics
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39
HowCanYouHelp?
Confidential|©2017RelayTherapeutics
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40
DockingChallengesHaveBecomeMoreChallenging
Confidential|©2017RelayTherapeutics
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Arewespendingenoughtimeunderstandcompoundsthatdockedpoorly?• Insufficientconformationalsampling• Insufficientposesampling• Inadequatescoring• LigandposeswithlimiteddensityIseveryonemissingthesamecompounds?Cangroupsworktogethertoimprovetheirmethods?
41
QuestionsonDockingChallenges
Confidential|©2017RelayTherapeutics
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D3RParticipantsCSARParticipantsTDTParticipantsSAMPLParticipants
RommieAmaroMikeGilson
MillLambertNeysaNevins
ConnorParksZiedGaieb
ShuaiLiu
42
Acknowledgements
Confidential|©2017RelayTherapeutics
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https://github.com/PatWalters/metk
OpenSourceEvaluationCode(MoretoCome)
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BACKUP
44Confidential|©2017RelayTherapeutics
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45
LooksLikeActivityPredictionisaSolvedProblem
Confidential|©2017RelayTherapeutics
0.82 0.80
0.66 0.65
Pearsonr
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46
WhatConstitutesanAppropriateNullModel
Confidential|©2017RelayTherapeutics
MolecularWeight XLogP SimpleQSAR
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47
WhatConstitutesanAppropriateNullModel
Confidential|©2017RelayTherapeutics
MolecularWeight XLogP SimpleQSAR
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48
Evaluatemaximumpossiblecorrelationforadatasetgivenexperimentalerror
Confidential|©2017RelayTherapeutics https://www.sciencedirect.com/science/article/pii/S1359644609000403
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StartwithexperimentaldataAddGaussianerror• Mean=0.0• Standarddeviation=0.3logCalculationcorrelationRepeat1000times
49
MaximumAchievableCorrelation
Confidential|©2017RelayTherapeutics