Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa...

39
Rotatable bonds in Drugs Ioniza3on vs Drug Permeability Henderson–Hasselbalch equa1on

Transcript of Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa...

Page 1: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

RotatablebondsinDrugsIoniza3onvsDrugPermeability

Henderson–Hasselbalchequa1on

Page 2: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

SolventAccessibleSurfaceArea(SASA)ofaroundhydrophobicatoms

•  Thehydrophobicenergycanbees3mated,whereσ issurfacetension20to40calA-2mol-1andAreaistheSolventAccessibleAreaaroundatomswithhydrophobicproper3es

•  Onemethylgroupburiesabout30A2thatcorrespondstoσ=0.6-1.2kcal/mol

Ehp =σ ⋅Areahp

Page 3: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

TypesofDrugIsomers

Newmanpj

ChirallypureRitalinThalidomideisomersOmepgazole/PrilosecvsNexium

•  IsomersofdrugswillactDIFFERENTLY•  Abilityand3mingtointerconvertdependsontheenergybarrierandiscri3calfordrugac3on

Chair/boat

Page 4: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Definingrotatablebonds•  Drugswithrotatablebondsundergoconforma3onalchanges

•  Rotatablebond:single,acyclic.•  Excludesinglebondstoaterminalatomorbondstolineargroups,e.g.CH3-C≡N.

•  Highlyrestrictedrota3on,e.g.esterlinkages.

•  SinglebondsinsidecyclesmayundergoRESTRICTEDROTATION(ringpuckering)

Torsionangle

Page 5: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Conforma3onalEntropyLossassociatedwithtargetbinding

•  Uponbindinglosesmostofitsrotamersandonlytheonecompa3blewiththebindingsiteischosen,italsolosestransla3onalandrota3onalDFs

•  Fullmethod:definealllowenergystatesandassignPi,

•  Simplemethodforcoun3ngrotamers:3perbond:3x3x3…

•  Simpleandadvancedentropices3mates

•  Realcoun3ngneedstoincludeenergy(clashing)andprobabilityes3mates

torsionsNrotN 3∝

Sconf _ entropy = R ln3Ntor = RNtor ln3 ≈ RNtor

Gconf _ entropy ≈ −RTNtor ≈ −0.6Ntor[kcal /mol]

Sconf _ entropy = −R Pi lntorsions∑ Pi

Smoleculeconf _ entropy = kB ln(NstatesIn1molecule )

Smoleconf _ entropy = R ln(NstatesIn1molecule ) =

−R ln(1 / N ) = −R (1 / N )N∑ ln(1 / N )

Smoleconf _ entropy = −R Pi lnstates∑ Pi

Page 6: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Popula3onsofconformers

•  Thepopula3onofdifferentconformersfollowsaBoltzmanndisribu3on

•  Consequencesfordrugbinding

•  UsingPiforentropycalculatons

•  Usingconforma3onalstrainEiintheenergybalancecalcula3onfordrugbinding

RTEE

j

iji

eNN −

−=

RTEE

j

iji

ePP −

−=

Sconf _ entropy = −R Pi lnstates∑ Pi

Page 7: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Posi3onalentropylossupondrugbinding:Entropyoffusion

•  Theentropylossuponcrystalliza3onfromtheliquidphasecanbees3matedasTΔS ~ 1.2-1.5 kcal/mol

•  enthalpyoffusion(mel3ng)forwater1.44,forethanol1.2

•  Asimilarentropylossisassociatedwiththedrugbinding

Page 8: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Mostdrugshaveionizablegroups

•  Fromabout55KdrugsinWDI,63%(~32K)areionizable.•  2/3rdshaveoneormorebasicgroup.

From:TimMitchellandRyszardKoblecki,MillenniumPharmaceu3calsLtd.

E.g.:Carboxylicacid

E.g.:Amine

Acid⇔H+ +Base

Page 9: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

AminesinDrugs:Examples

•  Chlorpheniramine:anan3histamine.•  Chlorpromazine:atranquillizer•  Ephedrineandphenylephrine:decongestants.•  Amphetamine,methamphetamine,andmethcathinone:

psychos3mulantamines•  Amitriptyline,imipramine,lofepramineandclomipramine:

tert.amines,tricyclicsad.•  Nortriptyline,desipramine,andamoxapine:secondary

amines,tricyclican3depressants

LonepairorH+dependingonthepH

Page 10: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

VariabilityofDrugAc3on•  Solubilityandabsorp3onofadrugarehighlyvariableandrequireoppositeproper3es

•  Itdependsonthechemicalnatureofthedrug,pH,concentra3ons

•  Dissolu3on,absorp3onanddistribu3ondependonthechargeofthedrug

•  Onlytheneutralformofadrugcanpassivelypermeatethemembrane

•  Everyexposedchargemaiers(ratherthanthemean).Zwiierionsdonothelp

•  Ac3vetransportmaychangethings:hijackingthebio-traffic

Page 11: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Absorp3on•  Transcellulartransportisthemostcommonwayofdrugabsorp3onanddistribu3on

•  Small~100-550andnonpolarcompoundscangothroughthetranscellularroute(logP>0)

•  Thebiggesteffect:ioniza1on.Polarity:thesecond

Source:Drugdiscoverytoday

BloodBrainBarrier.Astrocytessurroundingcapillariesinthebrain.Transportispassive(PSA<75)ortransporter-mediated

Page 12: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Acidity,BodyandDrugs

•  Litmustest(pHindicator)•  Itisallaboutthesmallestnucleus,asingleproton

belowpH4.5 abovepH8.3 4.5 ↔ 8.3

Litmusisawater-solublemixtureofdifferentdyesextractedfromlichens.Chemicalstructureof7-hydroxyphenoxazone,thechromophoreoflitmuscomponents

Lichens:Fungus+Algaorcyanobacterium

Page 13: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Mostatomsstaycovalentlybonded,buthydrogenisanexcep3on

Hydrogenionsjump:•  Betweenwatermolecules•  Betweendrugsandwatermolecules•  Betweenbothandacids/basesinsolu3on

Page 14: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Acid-BaseBalance•  NormalmetabolismproducesH+,(acidity)•  Dissocia3onofwater:2H2O→[OH-]+[H3O+],i.e.hydroxide+hydro[xo]niumions

•  High[H+]isacidic,low[H+]isbasic•  ThreeHomeosta3cmechanisms:–  Buffersystems,-instantaneous;temporary–  Exhala3onofCO2-operateswithinminutes;cannotcompletelycorrectseriousimbalances

–  Kidneyexcre3on-cancompletelycorrectanyimbalance(eventually)

+

Page 15: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Dealingwithahugerangeofconcentra3ons

Hydroxoniummolari1esrangefrom1to10-14M

Usethe“p”(power)operator:

p⇒−log10pH = −log10[H3

+O]

Page 16: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

pH•  pH(powerofHydrogenion)isameasureof[H3O+]molarity.

•  pH≡−log10[aH+],•  aH+isac3vityofwater•  aH+≈[H+],i.e.molarityofhydroxoniumions,inM=mol/L

•  Example:lemonadehas[H+]~0.005M,pH≈-log10(0.005)≈2.3

Page 17: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Self-ioniza3onofwater

•  2H2O→[OH-]+[H3O+]•  Kw=[H30+][OH-],dissocia3onconstantviamolari3esoftwoions.

•  Warning!Duetoaconven3on,KwisNOTastandardequilibriumconstant,sincethe[H2O]2isomiied.WatermolaritywillalsobeomiiedinKalater

•  Kw=10-14(mol/L)2

Page 18: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

LowpH,highpH

•  pHofpurewater[H3O+]=[OH-]=c:•  Kw=c2,,

[H3O+]purew=10-7M

•  pH=7•  LowpHmanyions•  HighpHfewions

Page 19: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Acid-BaseImbalances

•  Acidosis– Highblood[H+]– LowbloodpH,<7.35

•  Alkalosis– Lowblood[H+]– HighbloodpH,>7.45

Page 20: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Absorp3oninGItract

Stomach

1.4-2.1

3-7

Ileum

6.8-8.0

6.8-8.0

Colon

5-8

5-8

fastedstate

fedstate

Jejunum 4.4-6.65.2-6.2

0.1m2

0.3m2

Dressman,Amidon,Reppas,Shah,Pharm.Res.1998,15,11.

0.5-3.5hr 3-4hr

1-3d

120m2

acids bases

pH

Page 21: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

AcidsandBases

We’llconsideronlyBronstedequilibria.E.g.,

or,moregenerally,whichhastheacidityconstantKa([H2O]isomiied,asinKw)

-32 AcOHOH HAc +⇔+ +

NH4+ + H2O⇔ H3O

+ + NH3

BaseOHOH Acid 32 +⇔+ +

Ka =a H3O

+( )a Base( )a Acid( )

Page 22: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

pH,pKaandlog10

Nowusethe“p”operator:

10-logp⇒a10a -logp KK =

↑⇒↓ donatingproton p aK

][-logp 310 OHH +=

Page 23: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

pKaofsomefunc3onalgroups

phosphates(DNA)1.5,6.5purineN(DNA)9pyrimidineN(DNA)9carboxylates(a.a.,asp,glu,C-ter)3.5-5phenols(a.a.,tyr)9.5-11sul}ydryls(a.a.,cys)8.5hydroxyls(a.a.,ser,thr)13.5amines(DNA,ade,cyt)3.5-4imidazole(a.a.,his)6.5-7amino(a.a,lys,N-terminus)10guanidinium(a.a.,arg)13

Page 24: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Solubility•  Likedissolveslike•  Polarsolutesdissolveinpolarsolvents.

•  Nonpolarsolutesdissolveinnonpolarsolvents.

•  NeedtopredictormeasurepKa(s)sincechargedgroupshelpwatersolubilityandconflictwithfatsolubility.

µ 0aq + RT lnSW = µ 0s

From:LMLiu,A.LaioandA.MichaelidesPhys.Chem.Chem.Phys.,2011,13,13162

Page 25: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

DrugSolubility•  Foreachdrug,waterandfatsolubilityvary.•  Rela3vesolubili3esdependon

ChemicalstructureofthedrugpHofthesolu3onpKaofthedrug

•  Solubilitypercentagesdependonioniza3onra3os

Ace3c-acid-dissocia3on

Page 26: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

SolubilityandpKa

DrugpKa Solu1onpH

<7(Acidicsolu3on) >7(Basicsolu3on)

<7(Acidicdrug,chargeis-1or0)

pKa>pHUn-ionized,Fatsoluble

pKa<pH(-)Ionized,Watersoluble

>7(Basicdrug,chargeis0or+1)

pKa>pH(+)Ionized,Watersoluble

pKa<pH(0)Un-ionized,Fatsoluble

[H+]Excess [H+]Deficiency

Cau3on:Inmostinforma3onsourcesanddatabasesthedruggroupsionizedatpH=7.4groupswills3llbeshownasneutral.

Norepinephrineinitsunnaturalneutralform

Page 27: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Henderson-Hasselbalch•  ThedifferencebetweenthepHofthesolu3onandthepKaofthedrugisthecommonlogarithmofthera3oofionizedtounionizedformsofthedrug.

•  ForaciddrugsLog(Ionized/Unionized)=pH-pKa,or[I]/[U]=10(pH-pKa) Deriva1on:

Ka=[H+][A-]/[HA]-logKa=-log([H+][A-]/[HA])-logKa=-log[H+]-log([A-]/[HA])pKa=pH-log([A-]/[HA])log([A-]/[HA])=pH-pKa

Page 28: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

H.H.:aquan3ta3vepicture

•  Mostdrugsareweakacidsorweakbases

•  Itisnotallornothing,therearealwaysseveralspeciesatdifferentconcentra3ons pKapH

BHB

pKapHHAA

−=⎟⎟⎠

⎞⎜⎜⎝

+

−=⎟⎟⎠

⎞⎜⎜⎝

⎛ −

][][log

][][log

Page 29: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Frac3onIonizedasafunc3onofpKaandpH

+ -

0 0

Page 30: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Weakacidismostlyneutralinstomach

Adrugisaweakacid,hasapKaof5.5.Takenorally,itisinastomachsolu3onofpH3.5.

pH–pKa=3.5–5.5=-2Foranacid,weuse:ionized/unionized=10-2/1=1/100

Forevery1moleculeofthedrugthatisionized,100areunionized.Thisdruginthestomachishighlyfatsoluble.

Page 31: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

BasicDrugsForbasicdrugs,everythingisthe

sameexceptthatthera=oreverses:

Log(Unionized/Ionized)=pH–pKa

Examples:Chlorpheniramine,chlorpromazine,ephedrineandphenylephrine,amphetamine,methamphetamine,andmethcathinone,amitriptyline,imipramine,lofepramineandclomipramine,nortriptyline,desipramine,andamoxapine.

pKapHBHB

pKapHHAA

−=⎟⎟⎠

⎞⎜⎜⎝

+

−=⎟⎟⎠

⎞⎜⎜⎝

⎛ −

][][log

][][log

NH2+[Cl-]

Page 32: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Amphotericdrugs

•  Ordinaryampholytes,e.g.m-aminophenol•  pKaacidic>pKabasic.pKaA=9.8,pKaB=4.4•  IncreasingpH:1.NH3+2.Neutral3.O-

Page 33: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Zwiierionicampholytes

•  E.g.Aminoacids,pep3des

•  pKaacidic<pKabasic

Distribu3onofionicspeciesforthezwiierionicampholytelabetalol.fromA.Pagliara,P.-A.Carrupt,G.Caron,P.GaillardandB.Testa,Chem.Rev.,97,3385(1997).

Page 34: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

IsoelectricPoint•  pI=pH=½(pKaacidic+pKabasic)•  Itcanbebothunchargedandzwiierionicormul3plycharged

•  Forabsorp3oneverychargecounts(notthetotalcharge)

•  pIisusedforisoelectricfocusing(Agarosegelelectrophoresis)

Page 35: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Zwiieriondrugs:Examples

Page 36: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Calcula3onofthepHofdrugsolu3ons

•  Thedrugsolu3onitselfcandevelopitsownpH

•  ThepHcanbederivedfromitspKaandconcentra3on,C

Aweaklyacidicdrug:HA+H2O=[A-]+[H30+](1-a)cacaca–degreeofdissocia3on

a<<1ac=[H+]atc>≈10-7M

Note:thisapproxima=on

breaksatinfinitesimalconcentra=ons.

cpKpH a log21

21 −=

Ka =a2c2

(1− a)c≈ a2c

a2 = Ka / ca2c2 = Kac

[H+]= (Kac)12

− log([H+]) = − log((Kac)12 )

− log([H+]) = − log(Ka )− log(c)12

Deriva1on:

Forthesolu1onofaweaklyacidicdrug:

Note:loghereislog10

Page 37: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Weaklybasicdrugs•  Similarlyitcanbeshownthat

•  Example:codeinemonohydrate(MW=317.4),pKa=8.2

C=0.026MpH=7+4.1-0.79

cpKpHcpKpKpH

a

aw

log7log

21

21

21

21

21

++=

++=

BasicAmineischargedatneutralpH

Note:loghereislog10

Page 38: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

IonTrappingofanacidicdrugThesamehighlyfatsolubledrugreadilycrossesthestomachmembranesandentersbloodplasma,whichhasapHofapproximately7.5

pH–pKa=7.5–5.5=2[I]/[U]=102/1=100/1Forevery100moleculesofthedrugthatareionized,only1isunionized.Thedruginthebloodisnotveryfatsoluble.

Thisphenomenoniscallediontrapping.

Example:NaproxenpKa=5neutralinstomach(pH<5)(absorbed)chargedinblood(pH>7)

Page 39: Rotatable bonds in Drugs Ionizaon vs Drug Permeabilityruben.ucsd.edu/19/r15.pdfSolubility and pKa Drug pKa Soluon pH 7 (Basic solu3on)

Absorp3onisquan3ta3vetoo

•  Permea3onrate,RP=PAreaΔC•  Amountabsorbed=RP•Time

–  Pismembranepar33oncoefficient(relatedtoLogP)

–  Areaiseffec3vesurfaceareaofmembrane

–  ΔCisconcentra3ondifferencefortheneutralformofthedrug

•  Astomach/Aileumdiffer10003mes.Thatmeansthatevenifthefrac3onofneutralspeciesinstomachis1003mesgreater,s3ll103mesmorecompoundwillbeabsorbedinthegut.Theeffectof3mecomesontop.

Cout

Cin

A=120m2

A=0.1m2