chapter 13 part 3 drug design optimizing target interactions
TRANSCRIPT
Chapter 13 Part 3
Drug DesignOptimizing Target Interactions
1. Drug design - optimizing binding interactions
Aim - To optimize binding interactions with target
• 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
Reasons
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
C
CH3
CH3H3C
van der Waals interactions
LEAD COMPOUND
CH3
Hydrophobicpocket
Rationale:Rationale: Vary length and bulk of alkyl group to introduce selectivityVary length and bulk of alkyl group to introduce selectivity
2. Vary alkyl substituents
Fit
Fit
NCH3
N CH3 Fit
No Fit
StericBlock
N CH3
CH3
N
Binding region for N
Receptor 1 Receptor 2
Rationale: Vary length and bulk of alkyl group to introduce selectivity
2. Vary alkyl substituents
Example: Selectivity of adrenergic agents for -adrenoceptors over -adrenoceptors
2. Vary alkyl substituents
Propranolol(-Blocker)
OH
O NH
CH3
CH3H
Salbutamol (Ventolin) (Anti-asthmatic)
HOCH2
HO
HN
CCH3
OH
CH3
H
CH3
Adrenaline HO
HO
HN
CH3
OHH
-Adrenoceptor-Adrenoceptor
H-Bondingregion
H-Bondingregion
H-Bondingregion
Van der Waalsbonding region
Ionicbondingregion
ADRENALINEADRENALINE
-Adrenoceptor-Adrenoceptor
-Adrenoceptor-Adrenoceptor
-Adrenoceptor-Adrenoceptor
ADRENALINEADRENALINE
SALBUTAMOLSALBUTAMOL
-Adrenoceptor-Adrenoceptor
-Adrenoceptor-Adrenoceptor
-Adrenoceptor-Adrenoceptor
SALBUTAMOLSALBUTAMOL
SALBUTAMOLSALBUTAMOL
-Adrenoceptor-Adrenoceptor
SALBUTAMOLSALBUTAMOL
-Adrenoceptor-Adrenoceptor
SALBUTAMOLSALBUTAMOL
-Adrenoceptor-Adrenoceptor
SALBUTAMOLSALBUTAMOL
-Adrenoceptor-Adrenoceptor
SALBUTAMOLSALBUTAMOL
-Adrenoceptor-Adrenoceptor
SALBUTAMOLSALBUTAMOL
-Adrenoceptor-Adrenoceptor
-Adrenoceptor-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
O
R'
Drug O
H
Drug O
R"
Drug
Ether
HBra) NaHb) R"I
N
Me
Drug N
H
Drug N
R"
Drug
R R RAmine
VOC-Cl R"I
C
OR
Drug C
OH
Drug C
OR"
DrugO O O
Ester
HO- H+
R"OH
2. 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 OAmide
H+ HNR"2
Binding Region(H-Bond)
Binding Region(for Y)
para Substitution
Bindingsite
HO
Y
meta Substitution
Bindingsite
O
H
Y
3. Vary aryl substituents Vary substituents
Vary substitution pattern
WeakH-Bond
StrongH-Bond(increasedactivity)
3. Vary aryl substituents
Anti-arrhythmic activity best when substituent is at 7-position
Benzopyrans
6
7
8O
O
NR
MeSO2NH
Vary substituents
Vary substitution pattern
..
N
O
O
NH2
3. 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
..
NO
NH2
ON
O
NH2
O
Vary substituents
Vary substitution pattern
RECEPTORRECEPTOR
Rationale:Rationale: To explore target binding site for further binding
regions to achieve additional binding interactions
4. Extension - extra functional groups
Unusedbindingregion
DRUG
RECEPTORRECEPTOR
DRUGExtrafunctionalgroup
Binding regions
Binding group
DrugExtension
Example: ACE Inhibitors
4. Extension - extra functional groups
EXTENSION
Hydrophobic pocket
Bindingsite
NH
N
O CO2
O
O
CH3
Bindingsite
NH
N
O CO2
O
O
CH3
(I)
Hydrophobic pocket
Vacant
Example: Nerve gases and medicines
4. 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
PF
O(CHMe2)
CH3
Ecothiopate(medicine)
O
PS
N
CH3
H3C
H3C
OEt
OEt
Acetylcholine
ON
CH3
H3C
H3C
CH3
O
O
PS
N
CH3
H3C
H3C
OEt
OEt
Example: Second-generation anti-impotence drugs
4. Extension - extra functional groups
Notes:• Extension - addition of pyridine ring• Extra van der Waals interactions and HBA• Increased target selectivity
ViagraViagraN
N
CH3
S OO
CH3
N
HN
O
N
N
CH3
CH3
N
N
CH3
S OO
CH3
N
HN
O
N
HN
CH3
N
N
N
CH3
S OO
CH3
N
HN
O
N
HN
CH3
N
Example: Antagonists from agonists
4. Extension - extra functional groups
HO
HO
HN
CH3
OHH
Adrenaline
OH
O NH
CH3
CH3H
Propranolol(-Blocker)
NHN
NH2
Histamine
NHN
S
H3CHN
HNC
N
CH3
NHN
S
H3CHN
HNC
N
CH3
Cimetidine (Tagamet)(Anti-ulcer)
Rationale: • Useful if a chain is present connecting two binding groups
• Vary length of chain to optimise interactions
5. Chain extension / contraction
RECEPTORRECEPTOR
AA BBAA BB
RECEPTORRECEPTOR
Binding regions
Binding groupsA & BA & B
WeakWeakinteractioninteraction
StrongStronginteractioninteraction
Chain Chain extensionextension
Example: N-Phenethylmorphine
5. Chain extension / contraction
Optimum chain length = 2
HO
O
HO
N (CH2)n
H
Bindinggroup
Bindinggroup
HO
O
HO
N (CH2)n
H
Rationale:
To improve overlap of binding groups with their binding regions
6. Ring expansion / contraction
Hydrophobic regions
R R RR
Ringexpansion
Better overlap with hydrophobic interactions
Example:
6. Ring expansion / contraction
Binding regions
Binding siteBinding site Binding siteBinding site
Vary nto varyring size
NH
(CH2)n
N
N
CO2O
O2C
Ph
N
N
CO2ONH
Ph
O2CNH
N
N
CO2O
O2C
Ph
I
Three interactionsIncreased binding
Two interactionsCarboxylate ion out
of range
Rationale: • Replace aromatic/heterocyclic rings with other ring systems• Often done for patent reasons
7. Ring variations
General structurefor NSAIDS
X
X
Corescaffold
S
Br
F SO2CH3
N
N
CF3
F SO2CH3
F SO2CH3
DuP697
F SO2CH3
SC-58125
SC-57666
Rationale: Sometimes results in improved properties
7. Ring variations
Example:
Structure IStructure I(Antifungal agent)(Antifungal agent)
Cl
F
C
OHN
N
UK-46245UK-46245
Improved selectivityImproved selectivity
RingRingvariationvariation
Cl
F
C
OHN
NN
Structure I(Antifungal agent)
Cl
F
C
OHN
N
UK-46245Improved selectivity
Ringvariation
Cl
F
C
OHN
NN
Example - Nevirapine (antiviral agent)
7. Ring variations
N
HN
N
O
CO2tBu
Lead compound
N
HN
N N
O
CO2tBu
N
HN
N N
OMe
Nevirapine
Additionalbinding group
N
HN
N N
O
CO2tBu
Selective for -adrenoceptors
over -adrenoreceptors
Example - Pronethalol (-blocker)
7. Ring variations
R = Me AdrenalineR = H Noradrenaline
HO
HO
C
OHH
NHR
Pronethalol
HN
Me
OH
MeH
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
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
Propranolol (Propranolol (-blocker)-blocker)
OH
OH
NH
Me
Me
Propranolol (-blocker)
OH
OH
NH
Me
Me
Rationale for bio-isosteres:• Replace a functional group with another group which retains the same biological activity• Not necessarily the same valency
8. Isosteres and bio-isosteres
Example:Antipsychotics
Improved selectivity for D3 receptor over D2 receptor
Pyrrole ring =bio-isostere foramide group
Sultopride
EtO2S
OMe
O NH
NEt
DU 122290DU 122290
EtO2S
OMe
NH
NEt
DU 122290
EtO2S
OMe
NH
NEt
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
9. Simplification
OH
NHMe
OMe
HOOC
Ph
Cl
Drug
OH
NHMePh Drug
Excess ring
Methods:
9. Simplification
Example:
HO
O
HO
N CH3
HH
Morphine
HO
N CH3
HH
Levorphanol
HO
Me
Me
N CH3
HH
Metazocine
Remove excess rings
Excess functional groups
HO
O
HO
N CH3
HH
Morphine
YC
X H
Chiraldrug
YC
X H
Chiraldrug
Methods:
9. Simplification
YN
X
Achiraldrug
YC
X Y
Achiraldrug
Remove asymmetric center
Asymmetric center
Methods:
9. Simplification
Notes:• Simplification does not mean ‘pruning groups’ off the lead compound• Compounds usually made by total synthesis
A
OH
OH
NCH3
B
NCH3
OH
OH
C
OH
OH
NCH3
D
NCH3H
OH
OH
GLIPINE
OH
CH3 OH
H3C
NCH3
Simplify in stages to avoid oversimplification
Pharmacophore
GLIPINE
OH
CH3 OH
H3C
NCH3
Example:
•Important binding groups retained•Unnecessary ester removed•Complex ring system removed
9. 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
Disadvantages: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
9. Simplification
Target binding site
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
Different binding site leading to side effects
Rotatable bonds
Oversimplification of opioids
9. Simplification
MORPHINEMORPHINE
SIMPLIFICATIONSIMPLIFICATION
CC
C
CC
CO
N
LEVORPHANOLLEVORPHANOL
SIMPLIFICATIONSIMPLIFICATION
CC
C
CC
CO
N
LEVORPHANOLLEVORPHANOL
SIMPLIFICATIONSIMPLIFICATION
CC
C
CC
CO
N
METAZOCINEMETAZOCINE
SIMPLIFICATIONSIMPLIFICATION
CC
C
CC
CO
N
CC
C
CC
CO
N
OVEROVERSIMPLIFICATIONSIMPLIFICATION
CC
C
CC
CO
N
OVEROVERSIMPLIFICATIONSIMPLIFICATION
TYRAMINETYRAMINE
CC
C
CC
CO
N
OVEROVERSIMPLIFICATIONSIMPLIFICATION
AMPHETAMINEAMPHETAMINE
Note • Endogenous lead compounds are often simple and flexible • Fit several targets due to different active conformations• Results in side effects
10. 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
DisadvantageMolecule is more complex and may be more difficult to synthesise
Flexiblechain
single bondrotation
+ +
Different conformations
10. Rigidification
BONDROTATION
O H O2C
RECEPTOR 1
O H
O2C
RECEPTOR 2
O
H
H
NH2Me
ONH2Me
H
H
I
O
NH2Me
H
H
II
O
H
H
NH2Me
Methods - Introduce rings• Bonds within ring systems are locked and cannot rotate freely• Test rigid structures to see which ones have retained active conformation
10. Rigidification
FLEXIBLEMESSENGER
O
H
H
NH2Me
rotatable bonds
RIGID MESSENGER
O
NHMe
H
fixed bonds
10. Rigidification
HNX
CH3
X NHMe X
NHMe
X
MeN
X
NMe
X
NHMe
Introducingrings
Methods - Introduce rings• Bonds within ring systems are locked and cannot rotate freely• Test rigid structures to see which ones have retained active conformation
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
HNCH3
OH
O
HNCH3
Rigidification
Rotatable bonds
Rotatable Rotatable bondbond
Rotatable Rotatable bondbond
RingRingformationformation
RingRingformationformation
Methods - Introduce rigid functional groups
10. Rigidification
Flexiblechain
C NH
O
'locked' bonds
N
N
CO2H
O
Ar
N
O
CH3
HN
NH2
III
RigidRigid
Examples
10. Rigidification
Inhibitsplatelet aggregation
N
N
CO2H
NH
HN
NH2 O
O
Ar
guanidine
diazepine ring system
flexible chain
(I)
N
N
CO2H
O
O
NH
HN
NH2
Ar
II
Analogues
Important binding groups
N
N
CO2H
NH
HN
NH2 O
O
Ar
guanidine
diazepine ring system
flexible chain
(I)
RigidRigid
RigidRigid
N
N
CO2H
O
Ar
N
O
CH3
HN
NH2
III
Examples - Combretastatin (anticancer agent)
10. Rigidification
More active
Less active
Rotatablebond
H3CO
H3CO
OCH3
OCH3
OH
Combretastatin A-4
Z-isomerOH
H3CO
H3CO
OCH3
OCH3
OH
Combretastatin
H3CO
H3CO
OCH3
OCH3
OH
E-isomer
Methods - Steric Blockers
10. Rigidification
YX
Flexible side chain
X
Y
Coplanarity allowed
X
Y
CH3
Orthogonal ringspreferred
YX
CH3
steric block
Introduce steric block
X
Y
CH3
H
steric clash
Introduce steric block
X
CH3
Y
Unfavourable conformation
Stericclash
Stericclash
10. Rigidification
Increase in activityActive conformation retained
Serotonin antagonistN
HN
N
O
CF3
OMe
N
H
Introducemethyl group
N
HN
N
O
CF3
OMe
N
CH3
H
N
HN
N
O
CF3
OMe
NCH3 H
orthogonalrings
Methods - Steric Blockers
Steric clash
10. Rigidification
D3 Antagonist Inactive - active conformation disallowed
free rotation
N(CH2)4
HN
O
CF3O2SO
I
N(CH2)4
HN
O
CF3O2SO
Me
II
H
Methods – Steric Blockers
NN NNCH3
NN
HHNN
OO
10. Rigidification Identification of an active conformation by rigidification
NN NNCH3
NN
HHNN
OO
10. Rigidification Identification of an active conformation by rigidification
NN NNCH3
NN
HHNN
OO
10. Rigidification Identification of an active conformation by rigidification
NN NNCH3
NN
HHNN
OO
10. Rigidification Identification of an active conformation by rigidification
NN NNCH3
NN
HHNN
OO
10. Rigidification Identification of an active conformation by rigidification
NN NNCH3
NN
HHNN
OO
10. Rigidification Identification of an active conformation by rigidification
NN NNCH3
NN
HHNN
OO
10. Rigidification Identification of an active conformation by rigidification
10. Rigidification Identification of an active conformation by rigidification
Planar conformation
10. Rigidification Identification of an active conformation by rigidification
Orthogonal conformation
CYCLISATION
10. Rigidification Identification of an active conformation by rigidification
10. Rigidification Identification of an active conformation by rigidification
CYCLISATION
10. Rigidification Identification of an active conformation by rigidification
CYCLISATIONLocked into planar conformation
STERIC HINDRANCE
10. Rigidification Identification of an active conformation by rigidification
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
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
StrategyCarry out drug design based on the interactions between the lead compound and the target binding site
The design of novel agents based on a knowledge of the target binding site
12. De Novo 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• 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