1. DRUG DESIGN: OPTIMIZING TARGET INTERACTIONS
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 10
DRUG DESIGN:
OPTIMIZING TARGET INTERACTIONS
Part 1: Section 10.1 (SAR)

2. 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]

3. 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

4. 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

5. 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

6. 2.1 SAR on Alcohols Possible binding interactions Possible analogues
Drug
HBD O H
Drug
HBA X
Binding site H X
Binding site
X= N or O
Possible analogues
Ether
Ester
Alkane

7. 2.1 SAR on Alcohols Possible effect of analogues on binding
(e.g. ether) O
CH3
Ether analogue O
CH3
Ether analogue
steric shield X
Binding site
X= N or O H
No interaction as HBD
No interaction as HBA

8. 2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Possible binding interactions if amine is ionised
NH2R
Drug +
Ionic
CO2-
Binding site
H-Bonding N H
Drug R2 +
HBD
R3NH acts as a
strong HBD + X
Binding site
X= N or O

9. 2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Possible binding interactions for free base
H-Bonding N H
Drug R
HBD N R
Drug H
HBA X
Binding site H X
Binding site
X= N or O
Note:
3o Amines are only able to act as HBA’s - no hydrogen available to act as HBD

10. 2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Analogues of
1o & 2o amines
Effect on binding
CO2-
Binding site
No interaction N
CH3 O R
Amide
analogue
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)

11. 2.2 SAR on 1o, 2o & 3o Amines (RNH2, RNHR, R3N)
Analogues of 3o amines containing a methyl substituent

12. 2.3 SAR on Quaternary Ammonium Salts (R4N+)
Possible binding interactions
NR3
Drug +
NR3
Drug +
Ionic
bonding
Induced
dipole
interactions d+ d-
Binding site
CO2-
Binding site
Analogues
Full synthesis of 1o-3o amines and amides

13. 2.4 SAR on Aldehydes and Ketones
Possible binding interactions
Dipole-dipole
interaction O
Drug O
Drug
H-Bonding
HBA
Binding site (X= N or O) X H
Binding site
Analogues

14. 2.4 SAR on Aldehydes and Ketones
Effect on binding
Change in stereochemistry (planar to tetrahedral)
May move oxygen out of range
Binding site (X= N or O) X H OH
Alcohol
analogue
If still active, further reactions can be carried out on
alcohol to establish importance of oxygen

15. 2.5 SAR on Esters Possible binding interactions
H-bonding as HBA by either oxygen
Analogues
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

16. 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
Ester masking polar groups
allowing passage through
fatty cell membranes

17. 2.6 SAR on Amides Possible binding interactions
Drug H O R N
Drug H O R
HBD
HBA
Binding site (X= N or O) X H
Binding site (X= N or O) X
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

18. 2.6 SAR on Amides Analogues
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

19. 2.6 SAR on Amides Analogues
N-Methylation prevents HBD interaction and may introduce a steric effect that prevents an HBA interaction
Binding of O as HBA hindered X H N
CH3 R O
steric shield
Analogue
No binding as HBD X N
CH3 O R
Analogue
binding site

20. 2.7 SAR on Carboxylic Acids
Possible binding interactions as free acid C O H
Drug H C O
Drug
HBA
Binding site (X= N or O) X H
Binding site (X= N or O) X H
HBA C O H
Drug
HBD
Binding site (X= N or O) X

21. 2.7 SAR on Carboxylic Acids
Possible binding interactions as carboxylate ion O C
Drug - O C
Drug -
Ionic bonding
Binding site (X= N or O) X H
HBA
Binding site (X= N or O)
NHR2 +
Charged oxygen atoms are strong HBA’s
Group could interact both as an ion and as a HBA at the same time

22. 2.7 SAR on Carboxylic Acids
Possible analogues
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
H-Bonding hindered X H
steric shield C O
Analogue
CH3
No ionic bonding possible
NHR2
binding site C O
Analogue
CH3 +

23. 2.8 SAR on Aromatic Rings and Alkenes
Possible binding interactions
Drug
Drug R
binding site
binding site
vdw
hydrophobic
pocket
hydrophobic
region
vdw
Possible analogues

24. 2.8 SAR on Aromatic Rings and Alkenes
Possible effects on binding
Analogue H
Analogue R H
‘Buffers’
binding site
hydrophobic
pocket
binding site
hydrophobic
region No
fit

25. 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)

26. 2.10 SAR of Alkyl Groups Possible interactions Drug CH3 Drug CH3 H3C
hydrophobic slot
binding site
binding site
hydrophobic ‘pocket’
van der Waals
interactions

27. 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
Drug
Analogue