SAR

1. 3/10/2015
1
SAR
STRUCTURE - ACTIVITY
RELATIONSHIPS
(alkoholy, amíny, aldehydy,ketóny, estery, amidy, kyseliny, uhľovodíky)
MCH-II Andrej Boháč
Structure Activity Relationships (SAR)
•• aalterlter,, removeremove oror maskmask aa functionalfunctional groupgroup
•• ttestest thethe analogueanalogue forfor activityactivity
•• methodmethod ofof testingtesting
inin vitrovitro -- forfor binding interactionsbinding interactions withwith targettarget ((e.ge.g.. enzymeenzyme))
inin vivovivo -- forfor target binding interactionstarget binding interactions ++ pharmacokinetic propertiespharmacokinetic properties
•• ifif groupgroup isis removedremoved oror modifiedmodified andand inin vitrovitro activityactivity::
drops or diminisheddrops or diminished ==> group was> group was important forimportant for bindingbinding
unaffectedunaffected ==>> groupgroup isis notnot importantimportant
SARSAR -- identifiesidentifies which functional groups are importantwhich functional groups are important forfor
binding and activitybinding and activity
MethodMethod
ConsiderConsider byby aanaloguesnalogues::
•• modificationsmodifications may disrupt bindingmay disrupt binding stericsteric oror electronicelectronic
effectseffects
•• easiesteasiest analoguesanalogues areare thosethose made directlymade directly fromfrom a leada lead
compoundcompound
•• modificationsmodifications may depend on other groups presentmay depend on other groups present
•• ssomeome analoguesanalogues havehave to be made by ato be made by a fullfull (de novo)(de novo)
synthesissynthesis
((e.g. replacing an aromatic ring with ae.g. replacing an aromatic ring with a heterocyclicheterocyclic ringring))
•• SAR allowsSAR allows identification of important groups involvedidentification of important groups involved inin
bindingbinding
•• SAR allowsSAR allows identification ofidentification of the pharmacophorethe pharmacophore
O
NMe
HO
HO
MORPHINEMORPHINE
an opioid analgesic drugan opioid analgesic drug
55.. StructureStructure ActivityActivity RelationshipsRelationships (SAR)(SAR)
O
NMe
H3CO
HO
DROPSDROPSANALGESIC ACTIVITY
CODEINECODEINE
antitussive drugantitussive drug

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O
NMe
HO
HO
MORPHINEMORPHINE
O
NMe
HO
O
66--OXYMORPHINEOXYMORPHINE
ACTIVITY UNAFFECTEDACTIVITY UNAFFECTED
O
NMe
HO
HO
MORPHINEMORPHINE
IMPORTANTIMPORTANT GROUPSGROUPS DETERMINEDDETERMINED FORFOR ACTIVITYACTIVITY
N
HO
ANALGESIC PHARMACOPHORE FOR OPIATES
MORPHINE
O
NMe
HO
HO
NMe
HO
LEVORPHANOL
NMe
HO
METAZOCINE
CH3
H3C

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3
HBD
55..11 SARSAR onon AlcoholsAlcohols
PossiblePossible bindingbinding interactionsinteractions
PossiblePossible analoguesanalogues
X
Binding site
X= N or O
O
H
Drug
O
H
Drug
X
Binding site
H
HBA
EtherEther
EsterEster
AlkaneAlkane
PossiblePossible effecteffect ofof analoguesanalogues onon bindingbinding (e(e..gg.. ether)ether)
X
Binding site
X= N or O
X
Binding site
H
No interaction as HBD No interaction as HBA
steric shield
O
CH3
Ether analogue
O
CH3
Ether analogue
PossiblePossible bindingbinding interactionsinteractions ifif amineamine isis ionisedionised
55..22 SARSAR onon 11oo,, 22oo && 33oo AminesAmines (RNH(RNH22,, RNHR,RNHR, RR33N)N)
IonicIonic
HH--BondingBonding
HBD
X
Binding site
X= N or O
CO2
-
Binding site
NH2R
Drug
+
N
H
Drug
R2
+
R3NH acts as a
strong HBD
+
PossiblePossible bindingbinding interactionsinteractions forfor freefree basebase
HH--BondingBonding
HBD
X
Binding site
X= N or O
X
Binding site
H
HBA
N
H
Drug
R
N
R
Drug
H
NoteNote::
33oo AminesAmines areare onlyonly ableable toto actact asas HBA’sHBA’s -- nono hydrogenhydrogen availableavailable toto actact asas
HBDHBD

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AnaloguesAnalogues ofof
11oo && 22oo aminesamines
EffectEffect onon bindingbinding
CO2
-
Binding site
No interaction
N CH3
O
R
Amide
analogue
NotesNotes
••11oo andand 22oo aminesamines areare convertedconverted toto 22oo andand 33oo amidesamides respectivelyrespectively
•• aamidesmides cannotcannot ioniseionise andand soso ionicionic bondingbonding isis notnot possiblepossible
•• aann amideamide NN isis aa poorpoor HBAHBA andand soso thisthis eliminateseliminates HBAHBA interactionsinteractions
•• sstericteric effecteffect ofof acylacyl groupgroup isis likelylikely toto hinderhinder NNHH actingacting asas aa HBDHBD ((22oo
amide)amide)
R NH2
CH3COCl
R
H
N
O
CH3
AnaloguesAnalogues ofof 33oo aminesamines containingcontaining aa methylmethyl substituentsubstituent
R NHR
CH3COCl
R
R
N
O
CH3
R NHR
CH3
VOC-Cl
O CH3
O
Demethylation
2o
amine
3o
amide
A mistake, should be a chloride
PROPOSE A MECHANISM of demetylation from nitrogen?
PossiblePossible bindingbinding interactionsinteractions
AnaloguesAnalogues
FullFull synthesissynthesis ofof 11oo--22oo aminesamines andand subsequentlysubsequently amidesamides toto disabledisable
nitrogennitrogen toto formform ionion
55..33 SARSAR onon QuaternaryQuaternary AmmoniumAmmonium SaltsSalts (R(R44NN++))
CO2
-
Binding site
Ionic
bonding
NR3
Drug
+
NR3
Drug
+
Induced
dipole
interactions
Binding site
d+
d-
PossiblePossible bindingbinding interactionsinteractions
AnaloguesAnalogues
55..44 SARSAR onon AldehydesAldehydes andand KetonesKetones
Dipole-dipole
interaction
Binding site (X= N or O)
X
H
H-BondingHBA
O
Drug
Binding site
O
Drug
R R'
O
NaBH4 or
LiAlH4
R R'
HO H
Ketone
Planar sp 2
carbon centre
2o
Alcohol
Tetrahedral sp 3
carbon centre

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EffectEffect onon bindingbinding
ChangeChange inin stereochemistrystereochemistry ((planarplanar toto tetrahedraltetrahedral))
MayMay movemove oxygenoxygen outout ofof rangerange
IfIf stillstill active,active, furtherfurther reactionsreactions cancan bebe carriedcarried outout onon
alcoholalcohol toto establishestablish importanceimportance ofof oxygenoxygen
Binding site (X= N or O)
X
HH
OH
Alcohol
analogue
PossiblePossible bindingbinding interactionsinteractions
HH--bondingbonding asas HBAHBA byby eithereither oxygenoxygen
AnaloguesAnalogues
NotesNotes
••HydrolysisHydrolysis splitssplits moleculemolecule andand maymay leadlead toto aa lossloss ofof activityactivity duedue toto lossloss
ofof otherother functionalfunctional groupsgroups -- onlyonly suitablesuitable forfor simplesimple estersesters..
••HydrolysisHydrolysis leadsleads toto aa dramaticdramatic increaseincrease inin polaritypolarity whichwhich maymay influenceinfluence
abilityability ofof analogueanalogue toto reachreach targettarget ifif inin vivovivo teststests areare usedused
••ReductionReduction toto alcoholalcohol removesremoves carbonylcarbonyl groupgroup andand cancan establishestablish
importanceimportance ofof thethe carbonylcarbonyl oxygenoxygen,, butbut reactionreaction cancan bebe difficultdifficult toto dodo ifif
otherother labilelabile functionalfunctional groupsgroups areare presentpresent
55..55 SARSAR onon EstersEsters
R
C
O
O
CH3
LiAlH4
NaOH
R
C
OH
O
CH3HO
R
C
H2
OH
+
Carboxylic acid Alcohol
1o
Alcohol
NotesNotes
•• EstersEsters areare usuallyusually hydrolysedhydrolysed byby esterasesesterases inin thethe bloodblood
•• EstersEsters areare moremore likelylikely toto bebe importantimportant forfor
pharmacokineticpharmacokinetic reasonsreasons actingacting asas prodrugsprodrugs
Ester masks polar groupsEster masks polar groups
Allows passage throughAllows passage through
fatty cell membranesfatty cell membranes
C
O
O
R
ProdrugProdrug
O
C
R
O
ProdrugProdrug
FattyFatty
BarrierBarrier
C
O
O
R
O
C
R
O
C
OH
O
EsteraseEsterase
DrugDrug
OH
EsteraseEsterase
DrugDrug
PossiblePossible bindingbinding interactionsinteractions
NotesNotes
•• TheThe nitrogennitrogen ofof anan amideamide cannotcannot actact asas aa HBAHBA -- lonelone pairpair interactsinteracts
withwith carbonylcarbonyl groupgroup
•• TertiaryTertiary amidesamides unableunable toto actact asas HBD’sHBD’s
55..66 SARSAR onon AmidesAmides
Binding site (X= N or O)
X
H
Binding site (X= N or O)
X
HBA
HBD
N
Drug
H
O
R

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AnaloguesAnalogues
NotesNotes
•• hhydrolysisydrolysis splitssplits moleculemolecule andand maymay leadlead toto lossloss ofof activityactivity duedue toto
lossloss ofof otherother functionalfunctional groupsgroups -- onlyonly suitablesuitable forfor simplesimple amidesamides..
•• hhydrolysisydrolysis leadsleads toto dramaticdramatic increaseincrease inin polaritypolarity whichwhich maymay affectaffect
abilityability ofof analogueanalogue toto reachreach targettarget ifif inin vivovivo teststests areare donedone
•• rreductioneduction toto amineamine removesremoves carbonylcarbonyl groupgroup andand cancan establishestablish
importanceimportance ofof thethe carbonylcarbonyl oxygenoxygen,, butbut reactionreaction maymay bebe difficultdifficult toto dodo
ifif otherother labilelabile groupsgroups areare presentpresent
•• NN--alkylationalkylation willwill disabledisable HBDHBD propertiesproperties ofof NHNH groupgroup inin 22°° amidesamides
R
C
H
N
O
R'
LiAlH4
NaOH R
C
OH
O
R'H2N
R
C
H2
NH2
+
NaH / MeI
R
C
CH3
N
O
R'
Carboxylic acid Amine
1o
Amine
3o
Amide
••NN--MethylationMethylation prevents HBDprevents HBD interaction andinteraction and may introduce a stericmay introduce a steric
effecteffect that preventsthat prevents alsoalso anan HBA interactionHBA interaction
No binding as HBD
X
N
CH3
O
R
Analogue
binding site
Binding of O as HBA hindered
X
H
N
CH3
R
O
steric shield
Analogue
AnaloguesAnalogues
PossiblePossible bindingbinding interactionsinteractions asas freefree acidacid
55..77 SARSAR onon CarboxylicCarboxylic AcidsAcids
Binding site (X= N or O)
X
HHBA
Binding site (X= N or O)
X
H
HBA
C
O
H
Drug
O
C
O
H
Drug
O
Binding site (X= N or O)
X
HC
O
Drug
O
HBD
PossiblePossible bindingbinding interactionsinteractions asas carboxylatecarboxylate ionion
Binding site (X= N or O)
X
HHBA
Binding site (X= N or O)
NHR2+
Ionic bonding
O
C
O
Drug
-
O
C
O
Drug
-
NotesNotes
•• ChargedCharged oxygenoxygen atomsatoms areare strongstrong HBA’sHBA’s
•• GroupGroup cancan interactinteract byby ionicionic andand hydrogenhydrogen bondingbonding atat thethe samesame timetime

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PossiblePossible analoguesanalogues
PossiblePossible effectseffects
•• eesterificationsterification preventsprevents ionisation,ionisation, HBDHBD interactionsinteractions andand maymay hinderhinder HBAHBA
byby aa stericsteric effecteffect
•• rreductioneduction removesremoves carbonylcarbonyl oxygenoxygen asas potentialpotential HBAHBA andand preventsprevents
ionisationionisation
No ionic bonding possible
NHR2
binding site
C
O
O
Analogue
CH3
+
H-Bonding hindered
X
H
steric shield
C
O
O
Analogue
CH3
R
C
OH
O
LiAlH4
H+
/ R'OH R
C
OR'
O
R
C
H2
OH
Ester
1o
Alcohol
PossiblePossible bindingbinding interactionsinteractions
PossiblePossible analoguesanalogues
55..88 SARSAR onon AromaticAromatic RingsRings andand AlkenesAlkenes
binding site binding site
Drug
Drug
R R
hydrophobichydrophobic
regionregion
vdw
vdw
hydrophobichydrophobic
pocketpocket
H2 / Pd/C
H2 / RaNi
Drug Drug
H
R'H
R H
R'H
R
HH
PossiblePossible effectseffects onon bindingbinding
binding site
hydrophobichydrophobic
regionregion
binding site
hydrophobichydrophobic
pocketpocket
Analogue
H
H
No
fit
Analogue
R R
HH
‘Buffers’
PossiblePossible interactionsinteractions
55..1010 SARSAR ofof AlkylAlkyl GroupsGroups
hydrophobic slothydrophobic slot
binding site
Drug
CH3
van der Waals
interactions
binding site
hydrophobic ‘pocket’hydrophobic ‘pocket’
Drug
CH3
CH3
H3C

8. 3/10/2015
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AnaloguesAnalogues
EasiestEasiest alkylalkyl groupsgroups toto varyvary areare substituentssubstituents onon
heteroatomsheteroatoms
VaryVary lengthlength andand bulkbulk ofof alkylalkyl groupgroup toto testtest spacespace
availableavailable
55..1010 SARSAR ofof AlkylAlkyl GroupsGroups
N CH3
VOC-Cl
N H
R'X
N R'
HBr R'X
O
CH3
O
H
O
R'
Hydrolysis R'OH
C
OCH3
C
OH
O O H
C
OR'
O
Drug
Drug
Drug
Analogue
Analogue
Analogue
•• aacidcid chlorideschlorides -- tootoo reactivereactive toto bebe ofof useusedd
•• aacidcid anhydridesanhydrides -- tootoo reactivereactive toto bebe ofof useusedd
•• RXRX -- presentpresent inin anticanceranticancer drugsdrugs --reactreact withwith nucleophilesnucleophiles inin DNADNA
•• ArXArX -- commonlycommonly present.present. Not usually involved in bindingNot usually involved in binding directlydirectly
((withwith exceptionexception ofof halogenhalogen bondbond:: X....N,OX....N,O bondbond))
•• NONO22 -- sometimessometimes presentpresent butbut oftenoften toxictoxic
•• --C:::CC:::C-- aalkyneslkynes -- sometimessometimes present, butpresent, but not usually important innot usually important in
bindingbinding interactionsinteractions
•• --SH thiolsSH thiols -- presentpresent in some drugs asin some drugs as important binding group toimportant binding group to
transition metalstransition metals (e.g. Zn in zinc(e.g. Zn in zinc metalloproteinasesmetalloproteinases))
•• --CNCN -- presentpresent inin somesome drugsdrugs butbut rarelyrarely involvedinvolved inin bindingbinding
NotesNotes
•• ffunctionalunctional groupsgroups thatthat maymay bebe importantimportant forfor electronicelectronic reasonsreasons
((ee..gg.. nitro,nitro, cyanocyano,, arylaryl halides)halides)
•• ffunctionalunctional groupsgroups thatthat maymay bebe importantimportant forfor stericsteric reasonsreasons
((ee..gg.. alkynes)alkynes)
55..99 MiscellaneousMiscellaneous FunctionalFunctional GroupsGroups inin DrugsDrugs