drug-design-optimizing-target-interactions

1. Drug Design
Optimising Target Interactions

2. Optimising target interactions
• There are various aims in drug design, the drug
should
 Have a good selectivity for its target
 Have a good level of activity for its target
 Have minimum side effects
 Be easily synthesised
 Be chemically stable
 Have acceptable pharmacokinetics properties
 Be non-toxic

3. Binding Role of Different Functional Groups
• Functional groups such as alcohols, phenols,
amines, esters, amides, carboxylic acids, ketones
and aldehydes can interact with binding sites by
means of hydrogen bonding

4. Binding Role of Different Functional Groups
• Hydrogen bonding

5. Binding Role of Different Functional Groups
• Functional groups such as amines, (ionised)
quaternary ammonium salts and carboxylic acid
can interact with binding sites by ionic bond

6. Binding Role of Different Functional Groups
• Functional groups such as alkenes and aromatic
rings can interact with binding sites by means of
Van der Waals interactions

7. Binding Role of Different Functional Groups
• Alkyl substituents and the carbon skeleton of the
lead compound can interact with hydrophobic
regions of binding site by means of Van der
Waals interactions
• Interactions involving dipole moments or induced
dipole moments may play a role in binding a lead
compound to a binding site
• Reactive functional groups such as alkyl halides
may lead to irreversible covalent bonds being
formed between a lead compound and its target

8. Binding Role of Different Functional Groups
• Reactive functional groups such as alkyl halides
may lead to irreversible covalent bonds being
formed between a lead compound and its target

9. Optimising binding interactions
• Aim: to optimise binding interactions with target
• Reasons
 To increase activity and reduce dose levels
 To increase selectivity and reduce side effects
• Strategies
 Vary alkyl substituents
 Vary aryl substituents
 Extension

10. Optimising binding interactions
• Strategies
 Chain extensions / contractions
 Ring expansions / contractions
 Ring variation
 Isosteres
 Simplification
 Rigidification

11. Vary alkyl substituents
• The length and size of alkyl substituents can be
modified to fill up on hydrophobic pockets in the
binding site or to introduce selectivity for one
target over another
• Alkyl groups attached to heteroatoms are most
easily modified

12. 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
CH3
H3C
van der Waals
interactions
LEAD COMPOUND
CH3
Hydrophobic
pocket

13. Vary alkyl substituents
• Rationale:
 Vary length and bulk of alkyl group to introduce
selectivity
• Example: Selectivity of adrenergic agents for -
adrenoceptors over -adrenoceptors
Binding region for N
Receptor 1 Receptor 2
Fit
N CH3
Fit
N
CH3 CH3
N
N CH3
Fit
No Fit
Steric
block

14. Adrenaline
HO
HO
H
N
CH3
OH
H
Propranolol
(β-Blocker)
OH
O N
H
CH3
CH3
H
Salbutamol
HOCH2
HO
H
N CH3
OH
CH3
H
C
CH3
Vary alkyl substituents

15. 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

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

17. Vary alkyl substituents
• Methods
O
Drug
O
C R
O H
Drug O
Drug
O
C R”
Ester
R"COCl
OH-
Drug
O
C R
NH NH 2
Drug Drug
O
C R”
NH
Amide
R"COCl
C
Drug C
OH
Drug C
NR”2
Drug
O O O
Amide
NR2 H+ HNR”2
H+

18. Vary aryl substituents
• Aromatic substituents can be varied in character
and/or ring position
Binding Region
(H-Bond)
Binding Region
(for Y)
Weak
H-Bond
Strong
H-Bond
(increased
activity)
para-substitution
Binding
site
H
O
Y
Binding
site
O
H
Y
Meta-substitution

19. Vary aryl substituents
• Example: Benzopyrans
 Anti-arrhythmic activity best when substituent is
at 7-position
6
7
8
O
O
NR
MeSO2NH

20. Vary aryl substituents
• Binding strength of NH2 as HBD affected by
relative position of NO2
• Stronger when NO2 is at para position
N
O
O
NH2
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

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

22. Extension - extra functional groups
• Example: ACE (angiotensin-converting-enzyme)
inhibitors
EXTENSION
Binding
site
N
H
N
O CO2
O
O
CH3
Binding
site
N
H
N
O CO2
O
O
CH3
(I)
Hydrophobic pocket
Vacant
Hydrophobic pocket

23. Extension - extra functional groups
• Example: Nerve gases and medicines
 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)
H3C S
H C
N
3
CH3 O
P
S
N
CH3
H3C
3
H C
OEt
OEt
Acetylcholine
O
N
CH3
H3C
3
H C
CH3
O

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

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

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

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

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

29. Ring expansion / contraction
Binding regions
N
H
(CH2)n N
N
CO2
O
O2C
Ph
Binding site
N
N
CO2
O
N
H
Ph
O2C
Binding site
N
N
CO2
O
O2C
Ph N
H
I
Three interactions
Increased binding
Two interactions
Carboxylate ion out of range
Vary n to vary ring size

30. Ring variations
• Rationale
 Replace aromatic/heterocyclic rings with other
ring systems
 Done for patent reasons
General structure
for NSAIDS
X
X
Core
scaffold
S
Br
F SO2CH3
N
N
CF3
F SO2CH3
F SO2CH3
F SO2CH3

31. Ring variations
• Rationale
 Sometimes results in improved properties
UK-46245
Improved selectivity
Ring
variation
Structure I
(Antifungal agent)
Cl
F
C
OH
N
N
Cl
F
C
OH
N
N
N

32. Ring variations
• Example - Nevirapine (antiviral agent)
N
HN
N N
O
CO2
tBu
Additional
binding group
N
HN
N
O
CO tBu
2
Lead compound
N
HN
N N
O
Me
Nevirapine

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

34. Isosteres and bio-isosteres
• Rationale for isosteres
 Replace a functional group with a group of
same valency (isostere)
 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

35. Isosteres and bio-isosteres
• Example – Propanolol (β-blocker)
 Replacing OCH2 with CH=CH, SCH2, CH2CH2
eliminates activity
 Replacing OCH2 with NHCH2 retains activity
 Implies O involved in binding (HBA)
O
H
OH
NH
Me
Me

36. Isosteres and bio-isosteres
• Rationale for bio-isosteres
 Replace a functional group with another group
which retains the same biological activity
 Not necessarily the same valency

37. Isosteres and bio-isosteres
• Example – Antipsychotics
 Pyrrole ring = bio-isostere for amide group
Improved selectivity for
D3 receptor
over D2 receptor
Sultopride
EtO2S
O N
H
OMe
N
Et
EtO2S
N
H
OMe
N
Et
DU 122290

38. Simplification
• 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

39. Simplification
• Methods
 Retain pharmacophore
 Remove unnecessary functional groups
OH
NHMe
Ph Drug
OH
NHMe
OMe
HOOC
Ph
Cl
Drug

40. Simplification
• Methods
 Remove excess rings
Excess ring
Excess functional groups
HO
O
HO
N CH3
H
H
Morphine
HO
N CH3
H
H
Levorphanol
HO
Me N CH3
Me
H
H
Metazocine

41. Simplification
• Methods
 Remove asymmetric centre
Asymmetric center
Y
C
X H
Chiral
drug
Y
C
X H
Chiral
drug
Y
N
X
Achiral
drug
Y
C
X Y
Achiral
drug

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

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

44. Simplification
• Disadvantages
 Important binding groups retained
 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

45. MORPHINE
SIMPLIFICATION
C
C
C
C
C
C
O
N
Simplification
• Oversimplification of opioids

46. C
C
C
C
C
C
O
N
Simplification
• Oversimplification of opioids
LEVORPHANOL
SIMPLIFICATION

47. C
C
C
C
C
C
O
N
Simplification
• Oversimplification of opioids
METAZOCINE
SIMPLIFICATION

48. C
C
C
C
C
C
O
N
OVERSIMPLIFICATION
Simplification
• Oversimplification of opioids

49. C
C
C
C
C
C
O
N
TYRAMINE
OVERSIMPLIFICATION
Simplification
• Oversimplification of opioids

50. C
C
C
C
C
C
O
N
OVERSIMPLIFICATION
Simplification
• Oversimplification of opioids
AMPHETAMINE

51. Rigidification
• Endogenous lead compounds are often simple
and flexible
• Fit several targets due to different active
conformations
• Results in side effects

52. Rigidification
• Endogenous lead compounds are often simple
and flexible
• Fit several targets due to different active
conformations
• Results in side effects
single bond
rotation
+ +
Different conformations
Flexible
chain

53. 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

54. Rigidification
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
Bond rotation

55. Rigidification
Flexible messenger
O
H
H
NH2Me
Rigid messenger
O
NHMe
H
• Methods - Introduce rings
 Bonds within ring systems are locked and
cannot rotate freely
 Test rigid structures to see which ones have
retained active conformation
Rotatable bonds Fixed bonds

56. Rigidification
• Methods - Introduce rings
H
N
X
CH3
X NHMe X
NHMe
X
Me
N
X
NMe
X
NHMe
Introducing
rings
OH
OH
HN
CH3
OH
O
HN
CH3
Rigidification
Rotatable
bonds

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

58. Important
binding
groups
Rigidification
• Example
Rigid
Inhibits
platelet
aggregation
Analogues
Rigid
Rigid
N
N
CO2H
N
H
HN
NH2 O
O
Ar
Diazepine ring system
Guanidine Flexible chain
N
N
CO2H
O
Ar
O
N
CH3
HN
NH2
N
N
CO2H
O
O
N
H
HN
NH2
Ar

59. Rigidification
• Example - Combretastatin (anticancer agent)
Rotatable
bond
OH
3
H CO
H3CO
OCH3
OCH3
OH
Combretastatin
H3CO
H3CO
OCH3
OH
OCH3
Combretastatin A-4
More active
Z-isomer
3
H CO
H3CO
OCH3
OCH3
OH
E-isomer
Less active

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

61. Rigidification
• Methods - Steric Blockers
Increase in activity
Active conformation retained
Serotonin
antagonist
Introduce
methyl group
Steric
clash
N
H
N
N
O
CF3
OMe
N
CH3 H
Orthogonal ring
CF3
OMe
N
H
N
N
O
N
H
OMe
CH3
N
H
N
N
O
N
H
CF3

62. Rigidification
• Methods - Steric Blockers
D3 Antagonist
Inactive
(active conformation disallowed)
free rotation
N
H
(CH2)4 N
O
Steric clash
N
(CH ) H
2 4 N
O
Me
H
CF3O2SO
3 2
CF O SO

63. Structure-based drug design
Strategy
• Carry out drug design based on the interactions
between the lead compound and the target
binding site

64. Structure-based drug design
Procedure
• Crystallise target protein with bound ligand
• Acquire structure by X-ray crystallography
• Download to computer for molecular modelling
studies
• Identify the binding site
• Identify the binding interactions between ligand
and target

65. Structure-based drug design
Procedure
• Identify vacant regions for extra binding
interactions
• Remove the ligand from the binding site in silico
• ‘Fit’ analogues into the binding site in silico to
test binding capability
• Identify the most promising analogues
• Synthesise and test for activity
• Crystallise a promising analogue with the target
protein and repeat the process

66. De Novo Drug Design
• The design of novel agents based on a
knowledge of the target binding site
Procedure
• Crystallise target protein with bound ligand
• Acquire structure by X-ray crystallography
• Download to computer for molecular modelling
studies
• Identify the binding site
• Remove the ligand in silico

67. De Novo Drug Design
Procedure
• Identify potential binding regions in the binding
site
• Design a lead compound to interact with the
binding site
• Synthesise the lead compound and test it for
activity
• Crystallise the lead compound with the target
protein and identify the actual binding interactions
• Optimise by structure-based drug design