Transcript Drug Design Optimizing Target Interactions

Drug Design
Optimizing Target Interactions
Chapter 13 Part 3
1. Drug design - optimizing binding interactions
Aim - To optimize 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
• Chain extensions / contractions
• Ring expansions / contractions
• Ring variation
• Isosteres
• Simplification
• Rigidification
2. 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
LEAD COMPOUND
CH3
H3C
C
CH3
CH3
Hydrophobic
pocket
van der Waals
interactions
2. Vary
alkyl substituents
Rationale:
Vary length and bulk of alkyl group to introduce selectivity
N
CH3
N
CH3 Fit
Fit
No Fit
Fit
Receptor 1
N
CH3
N
CH3
Receptor 2
Binding region for N
Steric
Block
2. Vary
alkyl substituents
Rationale:
Vary length and bulk of alkyl group to introduce selectivity
Example:
Selectivity of
adrenoceptors
adrenergic
agents
for
b-adrenoceptors
over
a-
2. Vary
alkyl substituents
Adrenaline
H
HO
OH
H
N
CH3
HO
Salbutamol
(Ventolin)
(Anti-asthmatic)
H
HOCH2
OH
H
N
CH3
CH3
HO
Propranolol
(b-Blocker)
C
CH3
CH3
H
O
N
H
OH
CH3
a-Adrenoceptor
H-Bonding
region
H-Bonding
region
H-Bonding
region
Van der Waals
bonding region
Ionic
bonding
region
a-Adrenoceptor
ADRENALINE
a-Adrenoceptor
b-Adrenoceptor
ADRENALINE
b-Adrenoceptor
SALBUTAMOL
b-Adrenoceptor
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
2. 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.
2. Vary
alkyl substituents
Methods
R'
Drug
O
HBr
H
Drug
O
a) NaH
b) R"I
R"
Drug
O
Ether
Drug
Amine
Me
N
R
OR
Drug
Ester
C
O
VOC-Cl
H
Drug
N
R"I
R"
Drug
N
R
HO-
OH
Drug
C
O
R
H+
R"OH
OR"
Drug
C
O
2. Vary
alkyl substituents
Methods
O
O
C R
Drug
O
HO-
Drug
OH
R"COCl
C R"
Drug
O
Ester
O
Drug
O
C R
NH
H+
NR2
H+
Drug
NH2
R"COCl
Drug
C R"
NH
Amide
Drug
Amide
C
O
OH
Drug
C
O
HNR"2
NR2"
Drug
C
O
3.Vary aryl substituents
Vary substituents
Vary substitution pattern
Weak
H-Bond
Strong
H-Bond
(increased
activity)
H
O
H
O
Binding
site
Y
para Substitution
Binding Region
(H-Bond)
Binding
site
Y
meta Substitution
Binding Region
(for Y)
3. Vary aryl substituents
Vary substituents
Vary substitution pattern
O
MeSO2NH
6
7
8
O
NR
Benzopyrans
Anti-arrhythmic activity best when substituent is at 7-position
3. Vary aryl substituents
Vary substituents
Vary substitution pattern
..
..
NH2
NH2
NH2
O
N
N
O
Meta substitution:
Inductive electron
withdrawing effect
O
N
O
O
O
Para substitution:
Electron withdrawing effect due to
resonance + inductive effects
leading to a weaker base
Notes
• Binding strength of NH2 as HBD affected by relative position of NO2
• Stronger when NO2 is at para position
4. Extension - extra functional groups
Rationale:To explore target binding site for further binding
regions to achieve additional binding interactions
DRUG
Unused
binding
region
DRUG
Drug
Extension
RECEPTOR
Binding regions
Binding group
RECEPTOR
Extra
functional
group
4. Extension - extra functional groups
Example: ACE Inhibitors
Hydrophobic pocket
Hydrophobic pocket
Vacant
CH3
CH3
EXTENSION
N
O
O
N
H
Binding
site
O
O
(I)
CO2
N
N
H
Binding
site
O
O
CO2
4. Extension - extra functional groups
Example: Nerve gases and medicines
O(CHMe2)
F
P
CH3
O
Sarin
(nerve gas)
OEt
H3C
H3C
S
N
P
CH3
O
OEt
Ecothiopate
(medicine)
Notes:
• Extension - addition of quaternary nitrogen
H3C
• Extra ionic bonding interaction
H3C
• Increased selectivity for cholinergic receptor
• Mimics quaternary nitrogen of acetylcholine
O
CH3
N
CH3
O
Acetylcholine
4. Extension - extra functional groups
Example: Second-generation anti-impotence drugs
O
CH3
CH3
O
CH3
N
HN
H
N
HN
N
N
N
O
S
O
N
CH3
N
N
N
O
S
N
Viagra
CH3
Notes:
• Extension - addition of pyridine ring
• Extra van derWaals interactions and HBA
• Increased target selectivity
N
CH3
O
CH3
4. Extension - extra functional groups
Example: Antagonists from agonists
CH3
H
H
HO
OH
O
H
N
N
H
CH3
OH
CH3
HO
Propranolol
(b-Blocker)
Adrenaline
H3C
NH2
HN
N
S
HN
N
CH3
H
N
HN
C
N
Histamine
Cimetidine (Tagamet)
(Anti-ulcer)
5. Chain extension / contraction
Rationale:
• Useful if a chain is present connecting two binding groups
•Vary length of chain to optimise interactions
Weak
interaction
A
B
RECEPTOR
Chain
extension
A
RECEPTOR
Binding regions
A&B
Strong
interaction
Binding groups
B
5. Chain extension / contraction
Example: N-Phenethylmorphine
HO
O
N
(CH2)n
H
HO
Binding
group
Optimum chain length = 2
Binding
group
6. Ring expansion / contraction
Rationale:
To improve overlap of binding groups with their binding regions
Ring
expansion
R
R
R
R
Better overlap with
hydrophobic interactions
Hydrophobic regions
6. Ring expansion / contraction
Vary n
to vary
ring
size
Example:
Binding site
O 2C
Ph
(CH2)n
N
N
H
O
CO2
N
N
O2C
Ph
Binding site
N
I
O
N
O 2C
N
N
H
N
H
CO2
O
CO2
Ph
Binding regions
Two interactions
Carboxylate ion out of range
Three interactions
Increased binding
7. Ring variations
Rationale:
• Replace aromatic/heterocyclic rings with other ring systems
• Often done for patent reasons
F
SO2CH3
F
SO2CH3
N
X
N
S
X
Core
scaffold
F
Br
CF3
DuP697
SC-58125
SO2CH3
F
SO2CH3
General structure
for NSAIDS
SC-57666
7. Ring variations
Rationale:
Sometimes results in improved properties
Example:
N
N
N
N
N
OH
OH
C
C
Cl
Cl
F
Structure I
(Antifungal agent)
Ring
variation
F
UK-46245
Improved selectivity
7. Ring variations
Example - Nevirapine (antiviral agent)
O
O
HN
N
O
Me
HN
HN
N
N
t
CO2 Bu
Lead compound
N
N
N
CO2tBu
N
Additional
binding group
Nevirapine
N
7. Ring variations
Example - Pronethalol (b-blocker)
H
HO
OH
OH
H
C
NHR
H
N
Me
Me
HO
R = Me Adrenaline
R = H Noradrenaline
Pronethalol
Selective for badrenoceptors
over a-adrenoreceptors
8. Isosteres and bio-isosteres
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
8. Isosteres and bio-isosteres
Useful for SAR
Me
O
NH
Me
H
OH
Propranolol (b-blocker)
Notes
• Replacing OCH2 with CH=CH, SCH2, CH2CH2 eliminates activity
• Replacing OCH2 with NHCH2 retains activity
• Implies O involved in binding (HBA)
8. 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
Example:
Antipsychotics
N
Et
O
N
N
Et
N
H
OMe
EtO2S
H
OMe
EtO2S
Sultopride
DU 122290
Improved selectivity for D3
receptor over D2 receptor
Pyrrole ring =
bio-isostere for
amide group
9. 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
9. Simplification
Methods:
• Retain pharmacophore
• Remove unnecessary functional groups
Ph
Cl
OH
OH
HOOC
Drug
NHMe
OMe
Ph
Drug
NHMe
9. Simplification
Methods:
Remove excess rings
Example:
HO
HO
HO
O
N
CH3
N
H
H
H
H
CH3
N
Me
Me
H
H
HO
Morphine
Excess functional groups
Levorphanol
Excess ring
Metazocine
CH3
9. Simplification
Methods:
Remove asymmetric center
H
X
X
C
N
Y
Chiral
drug
Y
Asymmetric center
H
X
Ac hiral
drug
C
C
Y
Chiral
drug
Y
X
Y
Ac hiral
drug
9. Simplification
Methods:
Simplify in stages to avoid oversimplification
CH3
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H3C
N
N
CH3
GLIPINE
A
N
CH3
B
N
CH3
CH3
C
Pharmacophore
Notes:
• Simplification does not mean ‘pruning groups’ off the lead compound
• Compounds usually made by total synthesis
H
D
N
CH3
9. Simplification
Example:
Me
N
Et2NCH2CH2
CO2Me
O
H
Pharmacophore
C
O
O
COCAINE H
O
C
PROCAINE
NH2
•Important binding groups retained
•Unnecessary ester removed
•Complex ring system removed
9. Simplification
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
Target binding site
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Target binding site
Rotatable bonds
Different binding site leading to side effects
9. Simplification
Oversimplification of opioids
MORPHINE
C
C
O
C
C
C
C
N
SIMPLIFICATION
LEVORPHANOL
C
C
O
C
C
C
C
N
SIMPLIFICATION
LEVORPHANOL
C
C
O
C
C
C
C
N
SIMPLIFICATION
METAZOCINE
C
C
O
C
C
C
C
N
SIMPLIFICATION
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
TYRAMINE
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
AMPHETAMINE
C
C
O
C
C
C
C
N
OVERSIMPLIFICATION
10. Rigidification
Note
• Endogenous lead compounds are often simple and flexible
• Fit several targets due to different active conformations
• Results in side effects
single bond
rotation
+
+
Flexible
chain
Different conformations
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
10. Rigidification
H
NH2Me
H
O
O
NH2Me
H
H
BOND
ROTATION
I
II
O 2C
H
H
NH2Me
O
O
O H
NH2Me
H
RECEPTOR 1
O 2C
O H
H
RECEPTOR 2
10. 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
rotatable bonds
fixed bonds
H
H
O
O
NHMe
NH2Me
H
FLEXIBLE
MESSENGER
RIGID MESSENGER
10. 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
X
NHMe
Introducing
rings
H
N
X
NHMe
Me
N
X
CH3
X
X
X
NHMe
NMe
10. 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
OH
Rigidification
O
Rotatable
bonds
HN
HN
CH3
CH3
Rotatable
bond
Rotatable
bond
Ring
formation
Ring
formation
10. Rigidification
Methods - Introduce rigid functional groups
'locked' bonds
Flexible
chain
O
C
NH
10. Rigidification
Examples
CO2H
O
NH2
Important binding groups
HN
Inhibits
platelet
aggregation
N
N
H
guanidine
N
flexible chain
O
Ar
(I)
Analogues
diazepine ring system
NH2
CO2H
NH2
HN
CO2H
HN
O
O
N
H
N
N
N
O
CH3
Rigid
N
O
Ar
II
N
Rigid
III
Rigid
Ar
10. Rigidification
Examples - Combretastatin (anticancer agent)
Rotatable
bond
OCH3
OH
Z-isomer
H3CO
H3CO
H3CO
OH
E-isomer
H3CO
OCH3
OH
OCH3
Combretastatin A-4
More active
Less active
H3CO
H3CO
OCH3
OCH3
OH
OCH3
Combretastatin
10. Rigidification
Methods - Steric Blockers
X
Introduce
steric block
Y
X
Y
X
Y
CH3
steric block
Flexible side chain
Y
X
CH3
Introduce
steric block
Y
X
H
CH3
Coplanarity allowed
Unfavourable conformation
Y
X
steric
clash
Steric
clash
CH3
Orthogonal rings
preferred
10. Rigidification
Methods - Steric Blockers
H
N
O
H
N
N
CF3
N
Serotonin
antagonist
OMe
Introduce
methyl group
CH3
Steric
clash
H
N
O
N
H
N
N
CH3
H
N
CF3
N
OMe
O
H
N
orthogonal
rings
CF3
N
OMe
Increase in activity
Active conformation retained
10. Rigidification
Methods – Steric Blockers
Steric clash
Me
H
free rotation
CF3O2SO
(CH2)4
H
N
CF3O2SO
(CH2)4
N
N
O
II
H
N
O
I
D3 Antagonist
Inactive - active conformation disallowed
10. Rigidification
Identification of an active conformation by rigidification
N
N
CH3
N
HN
O
10. Rigidification
Identification of an active conformation by rigidification
N
N
CH3
N
HN
O
10. Rigidification
Identification of an active conformation by rigidification
N
N
CH3
N
HN
O
10. Rigidification
Identification of an active conformation by rigidification
N
N
CH3
N
HN
O
10. Rigidification
Identification of an active conformation by rigidification
N
N
CH3
N
HN
O
10. Rigidification
Identification of an active conformation by rigidification
N
N
CH3
N
HN
O
10. Rigidification
Identification of an active conformation by rigidification
N
N
CH3
N
HN
O
10. Rigidification
Identification of an active conformation by rigidification
Planar conformation
10. Rigidification
Identification of an active conformation by rigidification
Orthogonal conformation
10. Rigidification
Identification of an active conformation by rigidification
CYCLISATION
10. Rigidification
Identification of an active conformation by rigidification
CYCLISATION
10. Rigidification
Identification of an active conformation by rigidification
CYCLISATION
Locked into planar conformation
10. Rigidification
Identification of an active conformation by rigidification
STERIC HINDRANCE
10. Rigidification
Identification of an active conformation by rigidification
STERIC HINDRANCE
10. Rigidification
Identification of an active conformation by rigidification
STERIC HINDRANCE
10. Rigidification
Identification of an active conformation by rigidification
STERIC HINDRANCE
10. Rigidification
Identification of an active conformation by rigidification
STERIC HINDRANCE
Locked into orthogonal conformation
11. Structure-based drug design
Strategy
Carry out drug design based on the interactions between the lead
compound and the target binding site
Procedure
• Crystallize 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
• 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
12. 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
• 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