Accelera’ng Drug Discovery with Free Energy Calculaons on GPUs · comparable to other drug...
Transcript of Accelera’ng Drug Discovery with Free Energy Calculaons on GPUs · comparable to other drug...
Accelera'ngDrugDiscoverywithFreeEnergyCalcula'onsonGPUs
RobertAbelVP,Scien1ficDevelopment
DrugDiscovery• “It’sdamnedtoughtodiscoveradrug.”–EugeneCordes
• ThemissionofSchrödingerR&Distomakethismucheasier
LeadOp'miza'onisProfoundlyChallenging
PhaseofDrugDiscovery TotalCosts(USDmillions)
Target-to-hit $94Hit-to-lead $166
Lead-op1miza1on $414Preclinical $150PhaseI $273PhaseII $319PhaseIII $314
Submissiontolaunch $48Total $1,778
PaulSMetal.Nat.Rev.DrugDisc.9:203-214.2010.
FreeEnergyCalcula'onsShouldbeabletoHelp• Fasterpotencyop1miza1onwithfewersynthesizedcompounds
• Be]ermaintenanceofpotencywhiletuningADMETproper1es
• Accountforotherproper1esrelevanttoleadop1miza1on– Bindingselec1vity– Muta1onalresistance– Solubility– Membranepermeability
Rela'veBindingFreeEnergyCalcula'onswithFEP• Compu1ngrela1vefreeenergieshasnotableadvantages– Modelingofsmallerperturba1onsshouldbemoreaccurate
– Rela1vedifferencesareo`enofgreatestinterestinleadop1miza1on
• Insteadofmodelingthefullbindingprocess,weuseFEPtocompute– thedifferencebetweenligand1→2insolu1on(A)
– thedifferencebetweenligand1→2inthebindingsite(B)
ΔΔGbinding=ΔG1–ΔG2 =ΔGA–ΔGB
A
B
1 2
Schrödinger’sApproach:FEP+• Completesolu1oncombiningstate-of-the-artMDengine,samplingalgorithm,forcefield,so`wareengineering,andGPUsupportforunparalleledaccuracy,throughput,andeaseofuseinreal-lifeprospec1vedrugdiscoveryprojects
– Arou1nepartoftheporgolioofdesigntoolsusedbyinternalSchrödingerdrugdiscoverygroup
– Significantlyenriching1ghtbindersinallprospec1vestudies
– Con1nuouslydevelopedforaccuracyandperformanceimprovements
– Validatedacrosswiderangeofsystems– Scoringeachligandrequiresroughly1GPUdayofcompute?me
DesmondGPU• GPUcompu1ngprovidesasignificantadvantage
• Over200ligandsscoredw/iden1calprotocol• RMSE≈1kcal/mol,correla1onsappearpredic1ve
SchrödingerFEP+Retrospec'veAccuracy
|ΔΔGFEP–ΔΔGExpt.|(kcal/mol)
Percen
tage
46.2%
24.8%
15.4%
7.4% 6.2%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
<0.6 0.6-1.2 1.2-1.8 1.8-2.4 >2.4 -15
-14
-13
-12
-11
-10
-9
-8
-7
-6
-5
-4
-15 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4
BACECDK2JNK1MCL1P38PTB1BTHROMTYK2
ΔGFEP
(kcal/mol)
ΔGExpt.(kcal/mol)
FEP+—LWang,etal.JACS.,137:2695–2703.(2015)OPLS3—EHarder,etal.JCTC.,12:281–296.(2016)
Referencedpaper:LWang,etal.JACS.,137:2695–2703.(2015)
• Ourgoalisnotmerelytomakeaccuratepredic1ons
• Rather,ourgoalistodrivediscoveryprojectsforward
• Canwedothis?
Collabora'onA—Extremelyrapidop'miza'onofanewleadcompound
Rapidop'miza'onofaHTShitwithFEP+• Ahigh-throughputscreeniden1fiedaweakinhibitor(80μM)ofahigh-valuetarget
• Projectteamneededtodecideiftheinhibitorcouldbefurtherop1mizedtoprogresstheprojectfromleadiden1fica1ontoleadop1miza1on
• Collaboratorhadsynthesized73moleculestoimprovethepotencyoftheHTShit,butnoneweresa1sfactory
Rapidop'miza'onofaHTShitwithFEP+• Acrystalstructureoftheinhibitorshowedahighlyunusualbindingmode
• Collaboratorsuspectedthatunusualbindingmodemightgivetheinhibitorhighspecificity,ifpotencycouldbeop6mized
• Schrödingerwasgiven1weektodetermineiftherewasanyviableroutetoimprovethemolecule
Rapidop'miza'onofaHTShitwithFEP+• Usingin-houseandcloudcompu1ngresource~3500synthe1callyplausiblederiva1vemoleculeswerescored– ~100KGPUhours
• Only23ofthesemolecules(0.6%)werepredictedbyFEP+toboostthebindingpotencyoftheHTShit
• Thecollaboratorchosetoini1allyonlysynthesize3oftherecommended23molecules– Synthesiscosts,ifthemoleculesarechallenging,caneasilyexceed$5,000permolecule
– Synthesizingall3,500wouldnotbefeasibleformostdiscoveryprojects
Expt.Ki(μM)
26*
3.8
2.2
80
Rapidop'miza'onofaHTShitwithFEP+MoleculeR-groupFEP+Ki(μM)FEP+rankMMGBSArank
A 0.6 1 427
B 1.8 2 95
C 3.2 3 435
HTShit - - -
*Mixturewith3stereocenters,frac1onofeutomermaybe<<1/8
Rapidop'miza'onofaHTShitwithFEP+• UsingFEP+toguidecompoundsynthesis,thepotencyoftheHTShitwasimproved40xinasingleroundofchemistry
• UsingsimpleMM-GB/SAscoringthetop435compoundswouldhaveneededtobesynthesizedtorecoverthesetop3compounds
• Furtherop1miza1onofmoleculesBandCisnowalsoinprogress
Collabora'onB—simultaneousop'miza'onofpotency,selec'vity,andsolubility
FEP+usecasefromdiscoverycollabora'onB• Priortotheini1a1onofalarge-scaleFEPscreening
campaign(June2015),nomoleculeshadbeeniden1fiedwhichsimultaneouslyachievedhighpotency,selec1vity,andsolubility– Manymoleculesachievedpar1alsuccess,butno
moleculesweresa1sfactoryacrossallfourcriteria
• Star1nginJune2015,anunprecedentedFEPscoringcampaignwasini1atedtofindsa1sfactorymolecules– ~4000moleculesscoredbyFEPtodate(April2016)– Equivalentto>5yearsofwet-labexperimental
chemistrytotestallscoredideamolecules
• Goalwastomarryexpertmoleculardesignwithpredic1vescoringtoenabletheundertakingofchallengingsynthe1ctargets
Expt.EndPoint Mol.A Mol.B Mol.C Mol.D
Potency(pKi>9) ✔ ✔ ✔ ✔
Selec'vity1(>100x) ✔ ✔ ✗ ✗
Selec'vity2(>100x) ✔ ✗ ✔ ✔
Solubility(>20uM) ✗ ✔ ✔ ✗
FEP+usecasefromdiscoverycollabora'onB• TheFEPscoringcampaignhasbeenhugelysuccessful,with10moleculesnowsimultaneously
mee1ngpotency,selec1vityandsolubilitygoals:
• 46 FEP-recommended compounds were synthesized and 9 checked all four boxes
Molecule FEP Recommended
Date Synthesized
Potency (pKi > 9)
Selectivity 1 ( > 100x )
Selectivity 2 ( > 100x)
Solubility ( > 20 uM)
Mol. E Yes 11/4/15 ✔ ✔ ✔ ✔ Mol. F Yes 12/10/15 ✔ ✔ ✔ ✔ Mol. G Yes 12/10/15 ✔ ✔ ✔ ✔ Mol. H Yes 12/17/15 ✔ ✔ ✔ ✔ Mol. I No (Charged) 12/24/15 ✔ ✔ ✔ ✔ Mol. J Yes 12/28/15 ✔ ✔ ✔ ✔ Mol. K Yes 1/15/16 ✔ ✔ ✔ ✔ Mol. L Yes 1/21/16 ✔ ✔ ✔ ✔ Mol. M Yes 1/21/16 ✔ ✔ ✔ ✔ Mol. N Yes 3/16/16 ✔ ✔ ✔ ✔
FEP+usecasefromdiscoverycollabora'onB• Theparentcompound(Mol.D)ofmoleculesE,F,andGwasneitherhighlyselec1venorsoluble:
• MoleculesA,BandCwerefromadifferentsubseries,andcouldnotberelatedtomoleculesD,E,ForGthroughFEP+perturba1ons– Parallellarge-scaleop1miza1onofmul1plesubserieswasessen1altotheiden1fica1onofmoleculesE,F,andG
– Thesemoleculesweresynthe1callychallengingduetothechemistryofthecore,andwereunlikelytohavebeensynthesizedwithoutFEP+scoring
Core Core Core
Mol.D:pKi>9Selec.<100xSolub.<10µM
Mol.E,FandG:pKi>9Selec.>100xSolub.>20µM
Core
FEP+shoulddras'callyexpandthechemicalspaceexploredbydiscoveryprojectteams
• TrueimpactofFEP+willnotbeseenun1linvestmentinFEPiscomparabletootherdrugdiscoveryprojectcosts– Ideally,manythousandsofFEPcalcula1onsperproject– Ineffect,oneisabletoruna~100,000compoundmedicinalchemistryprojectinlessthanayear
– 100xincreaseinthroughputoveratypicaldiscoveryproject• Suchpredic1vescoringshouldenablemuchmorerapidop1miza1onandbalancingofligandproper1esthanwouldbeotherwisepossibleinleadop1miza1on
• Increasingthesuccessofpreclinicaldrugdiscoverymaybethemostpromisingavenuetobe]ermeettheurgentneedformoreeffec1vedrugtherapies
AcknowledgementsApplica'onsSciencesThijsBeumingDanielCappelOsamuIchiharaRoyKimuraAnaNegriDanielRobinsonWoodyShermanThomasSteinbrecher
LeadershipRamyFaridDrugDiscoveryGroupLeahFryeSarahBoyceMarkBrewerSatheshBhatJonathanGableJeremyGreenwoodKyleKonzeShaughnRobinsonMarkusDahlgrenFionaMcRobb
Scien'ficDevelopmentWolfgangDamnYuqingDengEdHarderJoeKausByungchanKimJenKnightGoranKrilovDavidLebardDimaLupyanSayanMondalLingleWangChuanjieWuYujieWuYutongZhaoChongkaiZhu
Scien'ficAdvisorsBruceBerneJohnChoderaRichFriesnerBillJorgensenDavidMobleyVijayPandeMarkMurckoD.E.ShawResearchMichaelBergdorfJus1nGullingsrudRossLippertCharlesRendlemanDanielleWhiteHuafengXu
Andenormousthankstoourcollaborators!
Q/A