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