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Optimizing Target Interactions
Stages of drug design and developmentStages of drug design and development
1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure-activity relationships (SAR) 6) Identify a pharmacophore 7) Drug design - optimizing target interactions 8) Drug design - optimizing pharmacokinetic properties 9) Toxicological and safety tests10) Chemical development and production11) Patenting and regulatory affairs12) Clinical trials
Structure-activity relationships (SAR)Structure-activity relationships (SAR)
• Alter, remove or mask a functional group
• Test the analogue for activity
• Conclusions depend on the method of testing•in vitro - tests for binding interactions with target•in vivo - tests for target binding interactions and/or pharmacokinetics
• If in vitro activity drops, it implies group is important for binding
• If in vivo activity unaffected, it implies group is not important
Aim - Aim - Identify which functional groups are important for binding and/or activity
MethodMethod
• Modifications may disrupt binding by electronic / steric effects
• Easiest analogues to make are those made from lead compound
• Possible modifications may depend on other groups present
• Some analogues may have to be made by a full synthesis(e.g. replacing an aromatic ring with a cyclohexane ring)
• Allows identification of important groups involved in binding
• Allows identification of the pharmacophore
Structure-activity relationships (SAR)Structure-activity relationships (SAR)
O
NMe
HO
HO
MORPHINEMORPHINE
Structure-activity relationships (SAR)Structure-activity relationships (SAR)
O
NMe
H3CO
HO
CODEINECODEINE
ACTIVITY DROPSACTIVITY DROPS
Structure-activity relationships (SAR)Structure-activity relationships (SAR)
O
NMe
HO
HO
MORPHINEMORPHINE
Structure-activity relationships (SAR)Structure-activity relationships (SAR)
O
NMe
HO
O
6-OXYMORPHINE6-OXYMORPHINE
ACTIVITY UNAFFECTEDACTIVITY UNAFFECTED
Structure-activity relationships (SAR)Structure-activity relationships (SAR)
O
NMe
HO
HO
MORPHINEMORPHINE
Important groups for activityStructure-activity relationships (SAR)Structure-activity relationships (SAR)
HBD
SAR on alcoholsSAR on alcohols
Possible binding interactionsPossible binding interactions
Possible analoguesPossible analogues
X
Binding site
X= N or O
OH
Drug
O
H
Drug
X
Binding site
H
HBA
R OH R OMeCH3I
CH3COClR
O
O
CH3
CH3SO2Cl
R SO
O
CH3
O
LiAlH4R H
EtherEther
EsterEster
AlkaneAlkane
Possible effect of analogues on bindingPossible effect of analogues on binding(e.g. ether)(e.g. ether)
X
Binding site
X= N or OX
Binding site
H
No interaction as HBD No interaction as HBA
steric shield
OCH3
Ether analogue
OCH3
Ether analogue
SAR on alcoholsSAR on alcohols
Possible binding interactions if amine is ionizedPossible binding interactions if amine is ionized
SAR on 1SAR on 1oo, 2, 2oo & 3 & 3oo amines amines (RNH(RNH22, RNHR, R, RNHR, R33N)N)
IonicIonic
H-BondingH-Bonding
HBD
X
Binding site
X= N or O
CO2-
Binding site
NH2R
Drug
+
NH
Drug
R2
+RR33NNHH acts as a acts as a strong HBDstrong HBD
+
Possible binding interactions for free basePossible binding interactions for free base
H-BondingH-Bonding
HBD
X
Binding site
X= N or OX
Binding site
H
HBA
NH
Drug
RN
R
Drug
H
Note: Note: 3o Amines are only able to act as HBA’s - no hydrogen available to act as HBD
SAR on 1SAR on 1oo, 2, 2oo & 3 & 3oo amines amines (RNH(RNH22, RNHR, R, RNHR, R33N)N)
Analogues ofAnalogues of11oo & 2 & 2oo amines amines
Effect on bindingEffect on binding
CO2-
Binding site
No interaction
N CH3
O
R
Amide analogue
NotesNotes• 1o and 2o amines are converted to 2o and 3o amides respectively• Amides cannot ionize and so ionic bonding is not possible• An amide N is a poor HBA and so this eliminates HBA interactions• Steric effect of acyl group is likely to hinder NH acting as a HBD (2o amide)
R NH2
CH3COCl
R
HN
O
CH3
SAR on 1SAR on 1oo, 2, 2oo & 3 & 3oo amines amines (RNH(RNH22, RNHR, R, RNHR, R33N)N)
Analogues of 3Analogues of 3oo amines containing a methyl substituent amines containing a methyl substituent
R NHRCH3COCl
R
RN
O
CH3R NHR
CH3
VOC-Cl
O CH3
O
Demethylation
2o amine
3o amide
SAR on 1SAR on 1oo, 2, 2oo & 3 & 3oo amines amines (RNH(RNH22, RNHR, R, RNHR, R33N)N)
Possible binding interactionsPossible binding interactions
AnaloguesAnalogues Full synthesis of 1o-3o amines and amides
SAR on quaternary ammonium salts SAR on quaternary ammonium salts (R(R44NN++))
CO2-
Binding site
Ionicbonding
NR3
Drug
+
NR3
Drug
+
Induceddipole interactions
Binding site
+-
Possible binding interactionsPossible binding interactions
AnaloguesAnalogues
SAR on aldehydes and ketonesSAR on aldehydes and ketones
Dipole-dipoleinteraction
Binding site (X= N or O)
XH
H-BondingHBA
O
Drug
Binding site
O
Drug
R R'
ONaBH4 or LiAlH4
R R'
HO H
KetonePlanar sp2
carbon centre
2o AlcoholTetrahedral sp3
carbon centre
Effect on bindingEffect on binding
Change in stereochemistry (planar to tetrahedral)May move oxygen out of range
If still active, further reactions can be carried out on alcohol to establish importance of oxygen
Binding site (X= N or O)
X
HH
OH
Alcoholanalogue
SAR on aldehydes and ketonesSAR on aldehydes and ketones
Possible binding interactionsPossible binding interactions H-bonding as HBA by either oxygenH-bonding as HBA by either oxygen
AnaloguesAnalogues
NotesNotes• Hydrolysis splits molecule and may lead to a loss of activity due to loss of other functional groups - only suitable for simple esters.
• Hydrolysis leads to a dramatic increase in polarity which may influence ability of analogue to reach target if in vivo tests are used
• Reduction to alcohol removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction can be difficult to do if other reactive functional groups are present
SAR on estersSAR on esters
RC
O
O
CH3
LiAlH4
NaOH RC
OH
O
CH3HO
RCH2
OH
+
Carboxylic acid Alcohol
1o Alcohol
NotesNotes• Esters are usually hydrolysed by esterases in the blood• Esters are more likely to be important for pharmacokinetic reasons i.e. acting as prodrugs
Ester masks polar groupsAllows passage throughfatty cell membranes
CO
O
R
ProdrugProdrug
OC
R
OProdrugProdrug
Fatty Fatty BarrierBarrier
CO
O
R
OC
R
O
COH
O
EsteraseEsteraseDrugDrug
OH
EsteraseEsteraseDrugDrug
SAR on estersSAR on esters
Possible binding interactionsPossible binding interactions
NotesNotes• The nitrogen of an amide cannot act as a HBA - lone pair interacts with neighboring carbonyl group• Tertiary amides unable to act as HBD’s
SAR on amidesSAR on amides
Binding site (X= N or O)
XH
Binding site (X= N or O)
X
HBAHBDN
Drug
H
O
RN
Drug
H
O
R
AnaloguesAnalogues
NotesNotes• Hydrolysis splits molecule and may lead to loss of activity due to loss of other functional groups - only suitable for simple amides.
• Hydrolysis leads to dramatic increase in polarity which may affect ability of analogue to reach target if in vivo tests are done
• Reduction to amine removes carbonyl group and can establish importance of the carbonyl oxygen, but reaction may be difficult to do if other reactive groups are present
SAR on amidesSAR on amides R
C
HN
O
R'
LiAlH4
NaOH RC
OH
O
R'H2N
RCH2
NH2
+
NaH / MeIR
C
CH3N
O
R'
Carboxylic acid Amine
1o Amine
3o Amide
SAR on amidesSAR on amides
• N-Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interaction
No binding as HBD
X
N
CH3
O
R
Analogue
binding site
Binding of O as HBA hindered
XH
N
CH3
R
O
steric shield
Analogue
AnaloguesAnalogues
Possible binding interactions as free acidPossible binding interactions as free acid
SAR on carboxylic acidsSAR on carboxylic acids
Binding site (X= N or O)
XHHBA
Binding site (X= N or O)
XH
HBAC
OH
Drug
O
C
OH
Drug
O
Binding site (X= N or O)
X
HC
O
Drug
O
HBD
Possible binding interactions as carboxylate ionPossible binding interactions as carboxylate ion
SAR on carboxylic acidsSAR on carboxylic acids
Binding site (X= N or O)
XHHBA
Binding site (X= N or O)
NHR2+
Ionic bonding
OC
O
Drug
-
OC
O
Drug
-
NotesNotes• Charged oxygen atoms are strong HBA’s• Group can interact by ionic and hydrogen bonding at the same time
Possible analoguesPossible analogues
Possible effectsPossible effects• Reduction removes carbonyl oxygen as potential HBA and prevents ionization• Esterification prevents ionization, HBD interactions and may hinder HBA by a steric effect
SAR on carboxylic acidsSAR on carboxylic acids
No ionic bonding possible
NHR2
binding site
C
O
O
Analogue
CH3
+
H-Bonding hindered
XH
steric shield
C
O
O
Analogue
CH3
RC
OH
O
LiAlH4
H+ / R'OH RC
OR'
O
RCH2
OH
Ester
1o Alcohol
Possible effects on bindingPossible effects on binding
binding sitehydrophobichydrophobicregionregion
binding site
hydrophobichydrophobicpocketpocket
Analogue
HH
Nofit
Analogue
R RHH
‘Buffers’
SAR on aromatic rings and alkenesSAR on aromatic rings and alkenes
• Acid chlorides - too reactive to be of use• Acid anhydrides - too reactive to be of use
• Alkyl halides - present in anticancer drugs -react with nucleophiles in DNA• Aryl halides - commonly present. Not usually involved in binding directly• Nitro groups - sometimes present but often toxic• Alkynes - sometimes present, but not usually important in binding interactions• Thiols - present in some drugs as important binding group to transition metals (e.g. Zn in zinc metalloproteinases)• Nitriles - present in some drugs but rarely involved in binding
Notes• Functional groups may be important for electronic reasons
(e.g. nitro, cyano, aryl halides)• Functional groups may be important for steric reasons
(e.g. alkynes)
Miscellaneous functional groups in drugsMiscellaneous functional groups in drugs
Possible interactionsPossible interactions
SAR of alkyl groupsSAR of alkyl groups
hydrophobic slothydrophobic slot
binding site
Drug
CH3
van der Waalsinteractions
binding site
hydrophobic ‘pocket’hydrophobic ‘pocket’
Drug
CH3CH3
H3C
AnaloguesAnalogues Easiest alkyl groups to vary are substituents on heteroatomsVary length and bulk of alkyl group to test space available
SAR of alkyl groupsSAR of alkyl groups
N CH3
VOC-ClN H
R'XN R'
HBr R'X
O
CH3O
HO
R'
Hydrolysis R'OH
C
OCH3C
OH
O O H
C
OR'
O
Drug
Drug
Drug
Analogue
Analogue
Analogue