Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 10

DRUG DESIGN:
OPTIMIZING TARGET
INTERACTIONS

Part 1: Section 10.1 (SAR)

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Contents

Part 1: Section 10.1 (SAR)

1. Introduction to drug design & development

2. Structure Activity Relationships (SAR) (2 slides)
2.1. SAR on Alcohols (2 slides)
2.2. SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N) (4 slides)
2.3. SAR on Quaternary Ammonium Salts (R4N+)
2.4. SAR on Aldehydes and Ketones (2 slides)
2.5. SAR on Esters (2 slides)
2.6. SAR on Amides (3 slides)
2.7. SAR on Carboxylic Acids (3 slides)
2.8. SAR on Aromatic Rings and Alkenes (2 slides)
2.9. Miscellaneous Functional Groups in Drugs
2.10. SAR of Alkyl Groups (2 slides)

[26 slides]

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 1. Introduction to drug design & development
Stages
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- optimising target interactions
8) Drug design - optimising pharmacokinetic properties
9) Toxicological and safety tests
10) Chemical development and production
11) Patenting and regulatory affairs
12) Clinical trials

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 2. Structure Activity Relationships (SAR)
AIM - Identify which functional groups are important for binding
and/or activity
METHOD
• 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

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2. Structure Activity Relationships (SAR)
NOTES ON ANALOGUES
• 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

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2.1 SAR on Alcohols

Possible binding interactions

Drug HBD Drug

HBA
H
O O H
X X
H
X= N or O

Binding site Binding site

Possible analogues
CH3I
R OH R OMe Ether
CH3COCl
O CH3
R Ester
O
CH3SO2Cl LiAlH4
O CH3
R S R H Alkane
OO

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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

Binding site Binding site

No interaction as HBD No interaction as HBA

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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Possible binding interactions if amine is ionised

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

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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Possible binding interactions for free base

H-Bonding
Drug HBD Drug
HBA
H
N N H
R H X
X R
X= N or O

Binding site Binding site

Note:
3o Amines are only able to act as HBA’s - no hydrogen available to act as HBD

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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Analogues of CH3COCl H
N CH3
R NH2
1o & 2o amines R

Effect on binding
Amide O
analogue
N CH3
R

CO2-

Binding site
No interaction

• 1o and 2o amines are converted to 2o and 3o amides respectively

• Amides cannot ionise 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)
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2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)

Analogues of 3o amines containing a methyl substituent

CH3 Demethylation CH3COCl R

N CH3
R NHR R NHR R
O
2o amine O
O CH3
3o amide
VOC-Cl

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2.3 SAR on Quaternary Ammonium Salts (R4N+)

Possible binding interactions

Drug
Drug Ionic
bonding Induced
dipole
+ interactions
NR3 -
NR3 +
+
CO2-

Binding site Binding site

Analogues
Full synthesis of 1o-3o amines and amides

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2.4 SAR on Aldehydes and Ketones

Possible binding interactions

Dipole-dipole
interaction

Drug HBA H-Bonding

Drug
O H
O
X

Binding site Binding site (X= N or O)

Analogues
O NaBH4 or LiAlH4
HO H
R R' R R'

Ketone 2o Alcohol
Planar sp 2 Tetrahedral sp 3
carbon centre carbon centre

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2.4 SAR on Aldehydes and Ketones
Effect on binding

Change in stereochemistry (planar to tetrahedral)

May move oxygen out of range
Alcohol
analogue

H H

X
OH

Binding site (X= N or O)

If still active, further reactions can be carried out on

alcohol to establish importance of oxygen

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2.5 SAR on Esters
Possible binding interactions
H-bonding as HBA by either oxygen
Analogues
R O R OH
NaOH C
C CH3 + HO CH3

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
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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

Prodrug Fatty Drug

barrier
esterase
O O OH
C R C R C

O O O

Prodrug Drug
O O esterase
C C
O R O R OH

Ester masking polar groups

allowing passage through
fatty cell membranes
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2.6 SAR on Amides

Possible binding interactions

Drug
Drug O
H N HBD
O HBA R
N
R H H
X X

Binding site (X= N or O) Binding site (X= N or O)

• The nitrogen of an amide cannot act as a HBA - lone pair

interacts with neighbouring carbonyl group
• Tertiary amides unable to act as HBD’s
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2.6 SAR on Amides
H
Analogues R
C
N
R'
NaOH R
C
OH
+ H2N R'
O O
Carboxylic acid Amine
LiAlH4 R NH2
C
H2
1o Amine

NaH / MeI CH3

R N
C R'
O
o
3 Amide

• 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

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2.6 SAR on Amides
Analogues

• N-Methylation prevents HBD interaction and may introduce a steric

effect that prevents an HBA interaction

Analogue
Analogue O
O
N R
N R steric shield CH3
CH3 H
X X

binding site

No binding as HBD Binding of O as HBA hindered

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2.7 SAR on Carboxylic Acids
Possible binding interactions as free acid

Drug
Drug O
C
O HBA
C H O
H H
HBA O H
X X

Binding site (X= N or O) Binding site (X= N or O)

Drug
O
C
O
H
HBD
X

Binding site (X= N or O)

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2.7 SAR on Carboxylic Acids
Possible binding interactions as carboxylate ion

Drug Drug

O O
C
C
- - Ionic bonding
O
HBA O H
X + NHR2

Binding site (X= N or O) Binding site (X= N or O)

• Charged oxygen atoms are strong HBA’s

• Group could interact both as an ion and as a HBA at the same
time

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2.7 SAR on Carboxylic Acids
R OH H+ / R'OH R OR'
C
Possible analogues C
O O
Ester

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
H
O +
CH3 NHR2 X

binding site

No ionic bonding possible H-Bonding hindered

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2.8 SAR on Aromatic Rings and Alkenes

Possible binding interactions

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'

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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

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 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

• 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)
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2.10 SAR of Alkyl Groups
Possible interactions

Drug Drug
van der Waals
interactions
binding site binding site

H3C CHCH3
3

hydrophobic ‘pocket’
hydrophobic slot
CH3

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2.10 SAR of Alkyl Groups
Analogues

• Easiest alkyl groups to vary are substituents on heteroatoms

• Vary length and bulk of alkyl group to test space available

VOC-Cl R'X
Drug N CH3 N H Analogue N R'

CH3 HBr H R'X R'

Drug O O Analogue O

OCH3 Hydrolysis OH R'OH OR'

Drug C C Analogue C
O O H O

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