Drug Design

Optimising Target Interactions

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
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
Binding Role of Different Functional Groups
Hydrogen bonding
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
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
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
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
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
Optimising binding interactions
Strategies
Chain extensions / contractions
Ring expansions / contractions
Ring variation
Isosteres
Simplification
Rigidification
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
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

LEAD COMPOUND ANALOGUE

CH3 C
H3C CH3
CH3

van der Waals

Hydrophobic interactions
pocket
Vary alkyl substituents
Rationale:
Vary length and bulk of alkyl group to introduce
selectivity
N No Fit N
CH3 Fit CH3
Steric
block
N CH3 Fit N CH3
Fit

Receptor 1 Receptor 2

Binding region for N

Example: Selectivity of adrenergic agents for b-

adrenoceptors over a-adrenoceptors
Vary alkyl substituents
OH
H H
HO N
CH3
Adrenaline
HO

OH
H H
HOCH2 N CH3
C
CH3
Salbutamol CH3
HO

CH3
H
Propranolol
O N CH3
(-Blocker) H
OH
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
Vary alkyl substituents
Methods
a) NaH
R' H b) R"I R
HBr
Drug O Drug O Drug O

Ether

Me H R"I R
VOC-CI
Drug N Drug N Drug N
R R R
Amine

OR OH H+ OR
OH-
Drug C Drug C Drug C
R"OH
O O O
Ester
Vary alkyl substituents
Methods
O O
C R OH- R"COCl C R
Drug O Drug OH Drug O

Ester

O O
C R H+ R"COCl C R
Drug NH Drug NH2 Drug NH

Amide

NR2 H+ OH HNR2 NR2

Drug C Drug C Drug C
O O O
Amide
Vary aryl substituents
Aromatic substituents can be varied in character
and/or ring position
Weak
H-Bond

H Strong
O H-Bond H
(increased Binding Region
activity) O (H-Bond)

Binding Region
Binding Binding (for Y)
site site
Y Y
para-substitution Meta-substitution
Vary aryl substituents
Example: Benzopyrans
O
MeSO2NH

7
O
8 NR

Anti-arrhythmic activity best when substituent is

at 7-position
Vary aryl substituents
..
NH2 NH2
..
NH2

O
N N
N
O O O O
O

Meta substitution: Para substitution

Inductive electron withdrawing Electron withdrawing effect due
effect to resonance
Inductive effects leading to a
weaker base

Binding strength of NH2 as HBD affected by

relative position of NO2
Stronger when NO2 is at para position
Extension - extra functional groups
Rationale: To explore target binding site for
further binding regions to achieve additional
binding interactions

Unused Extra
binding DRUG functional
DRUG region group

Drug
extension

RECEPTOR RECEPTOR

Binding regions
Binding group
Extension - extra functional groups
Example: ACE (angiotensin-converting-enzyme)
inhibitors
Hydrophobic pocket Hydrophobic pocket

Vacant

CH3 CH3
EXTENSION

O N O N
N N
H H
O O CO2 CO2
O O
Binding Binding
site (I) site
Extension - extra functional groups
Example: Nerve gases and medicines
O(CHMe2) OEt
F H3C S H3C O CH3
P N P N
CH3 H3C OEt H3C

O CH3 O CH3 O

Acetylcholine
Sarin Ecothiopate
(nerve gas) (medicine)

Extension: addition of quaternary nitrogen

Extra ionic bonding interaction
Increased selectivity for cholinergic receptor
Mimics quaternary nitrogen of acetylcholine
Extension - extra functional groups
Example: Second-generation anti-impotence
drugs CH O CH O 3
3 CH3
H
N N N
HN HN
N N
N N

O S O CH3 O S O CH3

N N

N Viagra N
CH3 CH3

Extension: addition of pyridine ring

Extra van der Waals interactions and HBA
Increased target selectivity
Extension - extra functional groups
Example: Antagonists from agonists
CH3
H

OH O N CH3
H
H H
HO N OH
CH3

HO
Adrenaline Propranolol
(-Blocker)

H3C CH3
H
NH2 N
S
HN HN
N N HN
C
N
Histamine
Cimetidine (Tagamet)
(Anti-ulcer)
Chain extension / contraction
Rationale
Useful if a chain is present connecting two
binding groups
Vary length of chain to optimise interactions
Weak Strong
interaction interaction
A B Chain A B
extension

RECEPTOR RECEPTOR

Binding regions
A&B Binding groups
Chain extension / contraction
Example: N-Phenethylmorphine
HO

O
N (CH2)n

H
HO
Binding Binding
group group

Optimum chain length = 2

Ring expansion / contraction
Rationale
To improve overlap of binding groups with their
binding regions

Ring
expansion

R
R R R

Hydrophobic regions Better overlap with

hydrophobic interactions
Ring expansion / contraction
O2C (CH2)n N
Vary n to vary ring size
N
Ph N
H
Binding regions O CO2

Binding site Binding site

O2C N N

N O 2C N
Ph N
H
N
O CO2 H O CO2
I
Ph

Two interactions Three interactions

Carboxylate ion out of range Increased binding
Ring variations
Rationale
Replace aromatic/heterocyclic rings with other
ring systems
Done for patent reasons
F SO2CH3 F SO2CH3

X
N
S N

Core Br CF3
F SO2CH3 F SO2CH3
scaffold
General structure
for NSAIDS
Ring variations
Rationale
Sometimes results in improved properties

N N
N
N OH
N OH
C
C
Cl
Cl

Ring
variation F
F

Structure I UK-46245
(Antifungal agent) Improved selectivity
Ring variations
Example - Nevirapine (antiviral agent)

O O O
Me
HN HN HN

N N N
N N N N N

Additional
t
CO2tBu CO2 Bu binding group
Lead compound Nevirapine
Ring variations
Example - Pronethalol (-blocker)
OH OH
H H H
HO C NHR N Me

Me
HO

R = Me Adrenaline Pronethalol
R = H Noradrenaline
Selective for -adrenoceptors
over a-adrenoreceptors
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
Isosteres and bio-isosteres
Example Propanolol (-blocker)
Me

O NH Me
H
OH

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
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
Pyrrole ring = bio-isostere for amide group

N N
Et Et
O N N Improved selectivity for
H H D3 receptor
OMe OMe over D2 receptor

EtO2S EtO2S

Sultopride DU 122290
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
Simplification
Methods
Retain pharmacophore
Remove unnecessary functional groups

HOOC OH OH

Ph Drug NHMe Ph Drug NHMe

Cl
OMe
Simplification
Methods
Remove excess rings

HO HO HO

N CH3 N CH3 Me N CH3

H H H
H H H
Me
HO

Morphine Levorphanol Metazocine

Excess functional groups Excess ring

Simplification
Methods
Remove asymmetric centre

X H X
C N
Y Y

Chiral Achiral
drug Asymmetric center drug

X H X Y
C C
Y Y

Chiral Achiral
drug drug
 Simplification
Methods
Simplify in stages to avoid oversimplification

OH OH OH OH OH

CH3 OH OH OH OH OH

H 3C
N N N N N
CH3 CH3 CH3 CH3 H CH3
GLIPINE A B C D

Pharmacophore

Simplification does not mean pruning groups

off the lead compound
Compounds usually made by total synthesis
Simplification
Example: procaine
Important binding groups retained
Unnecessary ester removed
Complex ring system removed
Me

N Et 2NCH 2CH2 O
CO 2Me
O C

H
O

O C
H
NH 2
COCAINE PROCAINE

Pharmacophore
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
Simplification
Oversimplification of opioids
C
O C MORPHINE
C

C
C
C

SIMPLIFICATION
Simplification
Oversimplification of opioids
C
O C LEVORPHANOL
C

C
C
C

SIMPLIFICATION
Simplification
Oversimplification of opioids
C
O C METAZOCINE
C

C
C
C

SIMPLIFICATION
Simplification
Oversimplification of opioids
C
O C
C

C
C
C

OVERSIMPLIFICATION
Simplification
Oversimplification of opioids
C
O C TYRAMINE
C

C
C
C

OVERSIMPLIFICATION
Simplification
Oversimplification of opioids
C
O C AMPHETAMINE
C

C
C
C

OVERSIMPLIFICATION
Rigidification
Endogenous lead compounds are often simple
and flexible
Fit several targets due to different active
conformations
Results in side effects
Rigidification
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
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
Rigidification
H NH2Me
H

O O

NH2Me Bond rotation

H H

I II

O 2C

H H
NH2Me
O O
O H O 2C O H
NH2Me

H H

RECEPTOR 1 RECEPTOR 2
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

Rigidification
Methods - Introduce rings
NHMe
Me
N
X NHMe X
H
X N Introducing X
CH3
rings

X X

NHMe
NMe

OH OH

Rigidification
OH O
Rotatable
bonds

HN HN
CH3 CH3
Rigidification
Methods - Introduce rigid functional groups

Flexible chain O
'locked' bonds
C NH
Rigidification
Example
CO2H

Important NH2 O

binding Inhibits
N
groups HN N
H
platelet
aggregation
N
Guanidine Flexible chain O

Ar

Diazepine ring system

NH2

CO2H CO2H
NH2
HN O
O
N
HN N
H N
N O
CH3
N
Rigid
N
Rigid
O
Rigid
Ar
Ar Analogues
 Rigidification
Example - Combretastatin (anticancer agent)
Rotatable
bond
OCH3
OH
H3CO
Z-isomer
H3CO H3CO
OH

H3CO H3CO
H3CO E-isomer
OCH3
OCH3 OCH3 Less active
OH
OH
OCH3
OCH3
Combretastatin A-4
More active Combretastatin
Rigidification
Methods - Steric Blockers
Introduce
X Y X Y X
steric block
Y
Steric
CH3 CH3
clash

steric block Unfavourable conformation

Flexible side chain

Y Introduce Y
Y

steric block
X
X X

H
CH3
CH3

steric
Coplanarity allowed clash Orthogonal rings
preferred
Rigidification
Methods - Steric Blockers
H O
H
N N
CF3
Serotonin
N
antagonist
N
OMe

Introduce
methyl group
Steric
clash
CH3
CH3 H O
H O N H
H N
N N CF3
CF3 N
N

N
N Orthogonal ring OMe
OMe

Increase in activity
Active conformation retained
 Rigidification
Methods - Steric Blockers

Steric clash
free rotation Me
H

H
CF3O2SO (CH 2)4 N
N H
CF3O2SO (CH 2)4 N
O N

D3 Antagonist
Inactive
(active conformation disallowed)
Structure-based drug design
Strategy
Carry out drug design based on the interactions
between the lead compound and the target
binding site
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
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
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
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