Created by Mohammad Rahsedul Haque. University of Dhaka. Department of Pharmaceutical Chemistry

1. Drug design
Improving target interactions (Pharmacodynamics)

2. Drug design - optimizing binding interactions
•To increase activity and reduce dose levels
•To increase selectivity and reduce side effects
Strategies Vary alkyl substituents
Vary aryl substituents
Extension
Chain extensions / contractions
Ring expansions / contractions
Ring variation
Isosteres
Simplification
Rigidification
Aim

3. Vary alkyl substituents
Rationale:
• Alkyl group in lead compound may interact with hydrophobic
region in binding site
• Vary length and bulk of group to optimise interaction
ANALOGUE
C
CH3
CH3H3C
van der Waals
interactions
LEAD COMPOUND
CH3
Hydrophobic
pocket

4. Rationale:
Vary length and bulk of alkyl group to introduce selectivity
Vary alkyl substituents
Fit
Fit
N
CH3
N CH3
Fit
No Fit
Steric
Block
N CH3
CH3
N
Binding region for N
Receptor 1 Receptor 2
Example:
Selectivity of adrenergic agents for b-adrenoceptors over a-
adrenoceptors

5. Vary alkyl substituents
Propranolol
(b-Blocker)
OH
O N
H
CH3
CH3
H
Salbutamol
(Ventolin)
(Anti-asthmatic)
HOCH2
HO
H
N
C
CH3
OH
CH3
H
CH3
Adrenaline HO
HO
H
N
CH3
OH
H

6. a-Adrenoceptor
H-Bonding
region
H-Bonding
region
H-Bonding
region
Van derWaals
bonding region
Ionic
bonding
region

7. ADRENALINE
a-Adrenoceptor

8. b-Adrenoceptor
ADRENALINE

9. a-Adrenoceptor
SALBUTAMOL

10. SALBUTAMOL
a-Adrenoceptor

11. Vary alkyl substituents
Synthetic feasibility of analogues
• Feasible to replace alkyl substituents on heteroatoms with other alkyl
substituents
• Difficult to modify alkyl substituents on the carbon skeleton of a lead
compound.

12. Vary alkyl substituents
Methods
O
R'
Drug O
H
Drug O
R"
Drug
Ether
HBr
a) NaH
b) R"I
N
Me
Drug N
H
Drug N
R"
Drug
R R R
Amine
VOC-Cl R"I
C
OR
Drug C
OH
Drug C
OR"
Drug
O O O
Ester
HO- H+
R"OH

13. Vary alkyl substituents
Methods
O
C
Drug
O
R
OHDrug O
C
Drug
O
R"
Ester
R"COClHO-
NH
C
Drug
O
R
NH2Drug NH
C
Drug
O
R"
Amide
R"COClH+
C
NR2
Drug C
OH
Drug C
NR2"
Drug
O O O
Amide
H+
HNR"2

14. Binding Region
(H-Bond)
Binding Region
(forY)
para Substitution
Binding
site
H
O
Y
meta Substitution
Binding
site
O
H
Y
Vary aryl substituents
Vary substituents
Vary substitution pattern
Weak
H-Bond
Strong
H-Bond
(increased
activity)

15. Vary aryl substituents
Anti-arrhythmic activity best when substituent is at 7-position
Benzopyrans
6
7
8
O
O
NR
MeSO2NH
Vary substituents
Vary substitution pattern

16. ..
N
O
O
NH2
Vary aryl substituents
Notes
• Binding strength of NH2 as HBD affected by relative position of NO2
• Stronger when NO2 is at para position
Meta substitution:
Inductive electron
withdrawing effect
Para substitution:
Electron withdrawing effect due to
resonance + inductive effects
leading to a weaker base
..
N
O
NH2
O
N
O
NH2
O
Vary substituents
Vary substitution pattern

17. RECEPTOR
Rationale: To explore target binding site for further binding
regions to achieve additional binding interactions
Extension - extra functional groups
Unused
binding
region
DRUG
RECEPTOR
DRUG
Extra
functional
group
Binding regions
Binding group
Drug
Extension

18. Example: ACE Inhibitors
Extension - extra functional groups
EXTENSION
Hydrophobic pocket
Binding
site
N
H
N
O CO2
O
O
CH3
Binding
site
N
H
N
O CO2
O
O
CH3
(I)
Hydrophobic pocket
Vacant

19. Example: Nerve gases and medicines
Extension - extra functional groups
Notes:
• Extension - addition of quaternary nitrogen
• Extra ionic bonding interaction
• Increased selectivity for cholinergic receptor
• Mimics quaternary nitrogen of acetylcholine
Sarin
(nerve gas)
O
P
F
O(CHMe2)
CH3
Ecothiopate
(medicine)
O
P
S
N
CH3
H3C
H3C
OEt
OEt
Acetylcholine
O
N
CH3
H3C
H3C
CH3
O
O
P
S
N
CH3
H3C
H3C
OEt
OEt

20. Example: Second-generation anti-impotence drugs
Extension - extra functional groups
Notes:
• Extension - addition of pyridine ring
• Extra van der Waals interactions and HBA
• Increased target selectivity
ViagraN
N
CH3
S OO
CH3
N
HN
O
N
N
CH3
CH3
N
N
CH3
S OO
CH3
N
HN
O
N
H
N
CH3
N
N
N
CH3
S OO
CH3
N
HN
O
N
H
N
CH3
N

21. Example: Antagonists from agonists
Extension - extra functional groups
HO
HO
H
N
CH3
OH
H
Adrenaline
OH
O N
H
CH3
CH3
H
Propranolol
(b-Blocker)
N
HN
NH2
Histamine
N
HN
S
H3C
H
N
HN
C
N
CH3
N
HN
S
H3C
H
N
HN
C
N
CH3
Cimetidine (Tagamet)
(Anti-ulcer)

22. Rationale:
• Useful if a chain is present connecting two binding groups
• Vary length of chain to optimise interactions
Chain extension / contraction
RECEPTOR
A B
A B
RECEPTOR
Binding regions
Binding groupsA & B
Weak
interaction
Strong
interaction
Chain
extension

23. Example: N-Phenethylmorphine
Chain extension / contraction
Optimum chain length = 2
HO
O
HO
N (CH2)n
H
Binding
group
Binding
group
HO
O
HO
N (CH2)n
H

24. Rationale:
To improve overlap of binding groups with their binding regions
Ring expansion / contraction
Hydrophobic regions
R R
R
R
Ring
expansion
Better overlap with
hydrophobic interactions

25. Example:
Ring expansion / contraction
Binding regions
Binding site Binding site
Vary n
to vary
ring
size
N
H
(CH2)n
N
N
CO2O
O2C
Ph
N
N
CO2O
N
H
Ph
O2C
N
H
N
N
CO2O
O2C
Ph
I
Three interactions
Increased binding
Two interactions
Carboxylate ion out of range

26. Rationale:
• Replace aromatic/heterocyclic rings with other ring systems
• Often done for patent reasons
Ring variations
General structure
for NSAIDS
X
X
Core
scaffold
S
Br
F SO2CH3
N
N
CF3
F SO2CH3
F SO2CH3
DuP697
F SO2CH3
SC-58125
SC-57666

27. Rationale:
Sometimes results in improved properties
Ring variations
Example:
Structure I
(Antifungal agent)
Cl
F
C
OHN
N
UK-46245
Improved selectivity
Ring
variation
Cl
F
C
OHN
NN
Structure I
(Antifungal agent)
Cl
F
C
OHN
N
UK-46245
Improved selectivity
Ring
variation
Cl
F
C
OHN
NN

28. Example - Nevirapine (antiviral agent)
Ring variations
N
HN
N
O
CO2
t
Bu
Lead compound
N
HN
N N
O
CO2
t
Bu
N
HN
N N
O
Me
Nevirapine
Additional
binding group
N
HN
N N
O
CO2
t
Bu

29. Selective for b-
adrenoceptors
over a-adrenoreceptors
Example - Pronethalol (b-blocker)
Ring variations
R = Me Adrenaline
R = H Noradrenaline
HO
HO
C
OH
H
NHR
Pronethalol
H
N
Me
OH
Me
H

30. Rationale for isosteres:
• Replace a functional group with a group of same valency (isostere)
e.g. OH replaced by SH, NH2, CH3
O replaced by S, NH, CH2
• Leads to more controlled changes in steric / electronic properties
• May affect binding and / or stability
Isosteres and bio-isosteres

31. Useful for SAR
Notes
• Replacing OCH2 with CH=CH, SCH2, CH2CH2 eliminates activity
• Replacing OCH2 with NHCH2 retains activity
• Implies O involved in binding (HBA)
Isosteres and bio-isosteres
Propranolol (b-blocker)
OH
O
H
NH
Me
Me
Propranolol (b-blocker)
OH
O
H
NH
Me
Me

32. Rationale for bio-isosteres:
• Replace a functional group with another group which retains the same
biological activity
• Not necessarily the same valency
Isosteres and bio-isosteres
Example:
Antipsychotics
Improved selectivity for
D3 receptor over D2
receptor
Pyrrole ring =
bio-isostere for
amide group
Sultopride
EtO2S
OMe
O N
H
N
Et
DU 122290
EtO2S
OMe
N
H
N
Et
DU 122290
EtO2S
OMe
N
H
N
Et

33. Rationale:
• Lead compounds from natural sources are often complex and difficult to
synthesize
• Simplifying the molecule makes the synthesis of analogues easier, quicker
and cheaper
• Simpler structures may fit the binding site better and increase activity
• Simpler structures may be more selective and less toxic if excess functional
groups are removed
Simplification

34. Methods:
• Retain pharmacophore
• Remove unnecessary functional groups
Simplification
OH
NHMe
OMe
HOOC
Ph
Cl
Drug
OH
NHMePh Drug

35. Excess ring
Methods:
Simplification
Example:
HO
O
HO
N CH3
H
H
Morphine
HO
N CH3
H
H
Levorphanol
HO
Me
Me
N CH3
H
H
Metazocine
Remove excess rings
Excess functional groups
HO
O
HO
N CH3
H
H
Morphine

36. Y
C
X H
Chiral
drug
Y
C
X H
Chiral
drug
Methods:
Simplification
Y
N
X
Achiral
drug
Y
C
X Y
Achiral
drug
Remove asymmetric center
Asymmetric center

37. Methods:
Simplification
Notes:
• Simplification does not mean ‘pruning groups’ off the lead compound
• Compounds usually made by total synthesis
A
OH
OH
N
CH3
B
N
CH3
OH
OH
C
OH
OH
N
CH3
D
N
CH3H
OH
OH
GLIPINE
OH
CH3 OH
H3C
N
CH3
Simplify in stages to avoid oversimplification
Pharmacophore
GLIPINE
OH
CH3 OH
H3C
N
CH3

38. Example:
•Important binding groups retained
•Unnecessary ester removed
•Complex ring system removed
Simplification
COCAINE
N
H
O
Me
C
CO2Me
H
O
PROCAINE
C
NH2
O
O
Et2NCH2CH2
Pharmacophore
COCAINE
N
H
O
Me
C
CO2Me
H
O
PROCAINE
C
NH2
O
O
Et2NCH2CH2

39. Disadvantages:
• Oversimplification may result in decreased activity and selectivity
• Simpler molecules have more conformations
• More likely to interact with more than one target binding site
• May result in increased side effects
Simplification

40. Note
• Endogenous lead compounds are often simple and
flexible
• Fit several targets due to different active conformations
• Results in side effects
Rigidification
Strategy
• Rigidify molecule to limit conformations - conformational restraint
• Increases activity - more chance of desired active conformation
being present
• Increases selectivity - less chance of undesired active conformations
Disadvantage
Molecule is more complex and may be more difficult to synthesise
Flexible
chain
single bond
rotation
+ +
Different conformations

41. Rigidification
BOND
ROTATION
O H O2C
RECEPTOR 1
O H
O2C
RECEPTOR 2
O
H
H
NH2Me
O
NH2Me
H
H
I
O
NH2Me
H
H
II
O
H
H
NH2Me

42. Methods - Introduce rings
• Bonds within ring systems are locked and cannot rotate freely
• Test rigid structures to see which ones have retained active conformation
Rigidification
FLEXIBLE
MESSENGER
O
H
H
NH2Me
rotatable bonds
RIGID MESSENGER
O
NHMe
H
fixed bonds

43. Rigidification
H
NX
CH3
X NHMe X
NHMe
X
Me
N
X
NMe
X
NHMe
Introducing
rings
Methods - Introduce rings
• Bonds within ring systems are locked and cannot rotate freely
• Test rigid structures to see which ones have retained active conformation

44. Rigidification
Methods - Introduce rings
• Bonds within ring systems are locked and cannot rotate freely
• Test rigid structures to see which ones have retained active
conformation
OH
OH
HN
CH3
OH
O
HN
CH3
Rigidification
Rotatable
bonds

45. Methods - Introduce rigid functional groups
Rigidification
Flexible
chain
C NH
O
'locked' bonds

46. N
N
CO2H
O
Ar
N
O
CH3
HN
NH2
III
Rigid
Examples
Rigidification
Inhibits
platelet
aggregation
N
N
CO2H
N
H
HN
NH2
O
O
Ar
guanidine
diazepine ring system
flexible chain
(I)
N
N
CO2H
O
O
N
H
HN
NH2
Ar
II
Analogues
Important binding groups
N
N
CO2H
N
H
HN
NH2
O
O
Ar
guanidine
diazepine ring system
flexible chain
(I)
Rigid
Rigid
N
N
CO2H
O
Ar
N
O
CH3
HN
NH2
III

47. Examples - Combretastatin (anticancer agent)
Rigidification
More active
Less active
Rotatable
bond
H3CO
H3CO
OCH3
OCH3
OH
Combretastatin A-4
Z-isomer
OH
H3CO
H3CO
OCH3
OCH3
OH
Combretastatin
H3CO
H3CO
OCH3
OCH3
OH
E-isomer

48. Methods - Steric Blockers
Rigidification
YX
Flexible side chain
X
Y
Coplanarity allowed
X
Y
CH3
Orthogonal rings
preferred
YX
CH3
steric block
Introduce
steric block
X
Y
CH3
H
steric
clash
Introduce
steric block
X
CH3
Y
Unfavourable conformation
Steric
clash

49. Steric
clash
Rigidification
Increase in activity
Active conformation retained
Serotonin
antagonistN
H
N
N
O
CF3
OMe
N
H
Introduce
methyl group
N
H
N
N
O
CF3
OMe
N
CH3
H
N
H
N
N
O
CF3
OMe
N
CH3 H
orthogonal
rings
Methods - Steric Blockers

50. Steric clash
Rigidification
D3 Antagonist Inactive - active conformation disallowed
free rotation
N
(CH2)4
H
N
O
CF3O2SO
I
N
(CH2)4
H
N
O
CF3O2SO
Me
II
H
Methods – Steric Blockers

51. N N
CH3
N
HN
O
Rigidification
Identification of an active conformation by rigidification

52. Rigidification
Identification of an active conformation by rigidification
Planar conformation

53. Rigidification
Identification of an active conformation by rigidification
Orthogonal conformation

54. Rigidification
Identification of an active conformation by rigidification
CYCLISATION

55. Rigidification
Identification of an active conformation by rigidification
STERIC HINDRANCE