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Drug Interaction Optimization (SAR)
Drug Interaction Optimization (SAR)
METHOD
Possible analogues
CH3I
R OH R OMe Ether
CH3COCl
O CH3
R Ester
O
CH3SO2Cl LiAlH4
O CH3
R S R H Alkane
OO
2.1 SAR on Alcohols
Possible effect of analogues on binding
(e.g. ether)
Ether analogue
Ether analogue steric shield
CH3
O
CH3
O H
X X
X= N or O
Drug
NH2R
+
Ionic CO2-
Binding site
H-Bonding
Drug HBD
+ H
+
N R3NH acts as a
R2
X strong HBD
X= N or O
Binding site
2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Possible binding interactions for free base
H-Bonding
Note:
3o Amines are only able to act as HBA’s - no hydrogen available to act as HBD
2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Analogues of CH3COCl H
N CH3
1o & 2o amines R NH2 R
Effect on binding
Amide O
analogue
N CH3
R
CO2-
Binding site
No interaction
Drug
Drug Ionic
bonding Induced
dipole
d+ interactions
NR3 d-
NR3 +
+
CO2-
Analogues
Full synthesis of 1o-3o amines and amides
2.4 SAR on Aldehydes and Ketones
Dipole-dipole
interaction
Analogues
O NaBH4 or LiAlH4
HO H
R R' R R'
Ketone 2o Alcohol
Planar sp2 Tetrahedral sp3
carbon centre carbon centre
2.4 SAR on Aldehydes and Ketones
Effect on binding
Alcohol
analogue
H H
X
OH
O O
Carboxylic acid Alcohol
LiAlH4 R OH
C
H2
1o Alcohol
• 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 labile functional groups are present
2.5 SAR on Esters
• Esters are usually hydrolysed by esterases in the blood
• Esters are more likely to be important for
pharmacokinetic reasons i.e. acting as prodrugs
O O O
Prodrug Drug
O O esterase
C C
O R O R OH
Drug
Drug O
H N
HBD
O HBA R
N
R H H
X X
• 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 labile
groups are present
2.6 SAR on Amides
Analogues
Analogue
Analogue O
O
N R
N R steric shield CH3
CH3 H
X X
binding site
Drug
Drug O
C
O HBA
C H O
H H
HBA O H
X X
Drug
O
C
O
H
HBD
X
Drug Drug
O O
C
C
- - Ionic bonding
O O
HBA H
X + NHR2
LiAlH4 R OH
C
H2
1o Alcohol
Possible effects
• Reduction removes carbonyl oxygen as potential HBA and prevents
ionisation
• Esterification prevents ionisation, HBD interactions and may hinder HBA
by a steric effect Analogue
Analogue
O
C
O O
C steric shield CH3
O + H
CH3 NHR2 X
binding site
Drug
Drug
R R
vdw
vdw binding site binding site
hydrophobic
hydrophobic region
pocket
Possible analogues
Drug Drug
H2 / RaNi
R H R H
H2 / Pd/C
H H
H R' H R'
2.8 SAR on Aromatic Rings and Alkenes
Possible effects on binding
Analogue
Analogue
‘Buffers’ R R
H H
H
H
No binding site binding site
fit hydrophobic
hydrophobic region
pocket
2.9 Miscellaneous Functional Groups in Drugs
• Acid chlorides - too reactive to be of use
• Acid anhydrides- too reactive to be of use
• Alkyl halides -present in anticancer drugs to form covalent bonds
with nucleophiles in target
• 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
Drug Drug
van der Waals
interactions
binding site binding site
H3C CHCH3
3
hydrophobic ‘pocket’
hydrophobic slot
CH3
2.10 SAR of Alkyl Groups
Analogues
VOC-Cl R'X
Drug N CH3 N H Analogue N R'