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
ANALOGUE

LEAD COMPOUND

CH3

H3C

CH3

CH3

Hydrophobic
pocket

van der Waals

interactions

Vary alkyl substituents

Rationale:
Vary length and bulk of alkyl group to introduce
selectivity
N

CH3 Fit
CH3 Fit

Receptor 1

No Fit

Fit

CH3

CH3
Steric
block

Receptor 2

Binding region for N

Example: Selectivity of adrenergic agents for adrenoceptors over -adrenoceptors

Vary alkyl substituents

H

HO

OH

H
N

Adrenaline

CH3

HO

HOCH2

Salbutamol

Propranolol
(-Blocker)

OH

H
N

CH3

CH3
CH3

HO

CH3

H
O
OH

N
H

CH3

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
R'
Drug

HBr

H
Drug

a) NaH
b) R"I

R
O

Drug

Ether

Me
Drug

OR

Ester

H
Drug

Drug
R

OH

OHDrug

R"I

Amine

Drug

VOC-CI

C
O

OR

H+
R"OH

Drug

C
O

Vary alkyl substituents

Methods
O

O
C

Drug

R OH-

R"COCl
Drug

OH

Drug

Ester

O
C

Drug

R H+

NH

R"COCl
Drug

NH2

Drug

NH

Amide

NR2
Drug
Amide

OH

H+
Drug

NR2

HNR2
Drug

C
O

Vary aryl substituents

Aromatic substituents can be varied in character
and/or ring position
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)

Vary aryl substituents

Example: Benzopyrans
O

MeSO2NH
6
7
8

NR

Anti-arrhythmic activity best when substituent is at

7-position

Vary aryl substituents

..

NH2

NH2

..

NH2

O
O

Meta substitution:
Inductive electron withdrawing
effect

Para substitution
Electron withdrawing effect due 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

DRUG

Unused
binding
region

DRUG
Drug
extension

RECEPTOR

Binding regions
Binding group

RECEPTOR

Extra
functional
group

Extension - extra functional groups

Example: ACE (angiotensin-converting-enzyme)
inhibitors
Hydrophobic pocket

Hydrophobic pocket

Vacant

CH3
O

Binding
site

EXTENSION

CH3

N
H
O

O
(I)

O
CO2

Binding
site

N
H
O

CO2

Extension - extra functional groups

Example: Nerve gases and medicines
F

O(CHMe2)
P

CH3

Sarin
(nerve gas)

H3C
H3C

CH3

OEt
P
O

Ecothiopate
(medicine)

OEt

H3C
H3C

N
CH3

CH3

Acetylcholine

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
O
CH
CH
3

HN

HN

CH3

CH3

H
N

Viagra

CH3

N
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

HO

OH

H
N

OH

Propranolol
(-Blocker)

Adrenaline

H3C
HN

Histamine

CH3

CH3

HO

NH2

N
H

HN

S
N

CH3

H
N
HN

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
interaction
A

Strong
interaction
Chain
extension

RECEPTOR

RECEPTOR
Binding regions
A&B

Binding groups

Chain extension / contraction

Example: N-Phenethylmorphine
HO

O
N

(CH2)n

H
HO

Binding
group

Binding
group

Optimum chain length = 2

Ring expansion / contraction

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

Hydrophobic regions

Better overlap with

hydrophobic interactions

Ring expansion / contraction

O2C
Ph

Binding regions

(CH2)n

Vary n to vary ring size

N
H
O

CO2

Binding site

O2C
Ph

Binding site

O 2C

N
H

N
H

CO2

Two interactions
Carboxylate ion out of range

CO2

Ph

Three interactions
Increased binding

Ring variations
Rationale
Replace aromatic/heterocyclic rings with other
ring systems
Done for patent reasons
F

SO2CH3

SO2CH3

X
X

N
N

Core
scaffold

General structure
for NSAIDS

Br

SO2CH3

CF3

SO2CH3

Ring variations
Rationale
Sometimes results in improved properties
N

N
N

N
N

OH

OH
C

Cl

Cl

Structure I
(Antifungal agent)

Ring
variation

UK-46245
Improved selectivity

Ring variations
Example - Nevirapine (antiviral agent)
O

O
HN

HN

N
CO2tBu

Lead compound

Me

N
t

CO2 Bu

HN

Additional
binding group

Nevirapine

Ring variations
Example - Pronethalol (-blocker)
H
HO

OH
C

NHR

OH

Me
Me

HO

R = Me Adrenaline
R = H Noradrenaline

H
N

Pronethalol

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

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
Et
N

H
OMe

EtO2S

H
OMe

EtO2S

Sultopride

N
Et

DU 122290

Improved selectivity for

D3 receptor
over D2 receptor

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
OH

HOOC
Ph
Cl

Drug

NHMe
OMe

OH
Ph

Drug

NHMe

Simplification
Methods
Remove excess rings
HO

HO

HO

CH3
H

HO

Morphine

Levorphanol

Excess functional groups

CH3

Me
Me

Metazocine

Excess ring

CH3

Simplification
Methods
Remove asymmetric centre
H

X
C

Chiral
drug

Asymmetric center
H

X
C
Chiral
drug

X
Y

Achiral
drug
Y

X
C

Y
Achiral
drug

Simplification
Methods
Simplify in stages to avoid oversimplification

CH3
H3 C

GLIPINE

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

CH3

CH3

CH3

CH3

CH3

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

CO 2Me

O
C

O
O

COCAINE

PROCAINE

Pharmacophore

NH 2

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

MORPHINE

C
C
C

SIMPLIFICATION

Simplification
Oversimplification of opioids
C

LEVORPHANOL

C
C
C

SIMPLIFICATION

Simplification
Oversimplification of opioids
C

METAZOCINE

C
C
C

SIMPLIFICATION

Simplification
Oversimplification of opioids
C

C
C
C

OVERSIMPLIFICATION

Simplification
Oversimplification of opioids
C

TYRAMINE

C
C
C

OVERSIMPLIFICATION

Simplification
Oversimplification of opioids
C

AMPHETAMINE

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

O
NH2Me

Bond rotation

II
O 2C

H
O H

O
NH2Me
H

RECEPTOR 1

O 2C

O H

NH2Me

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

O
NHMe

NH2Me
H

Flexible messenger

Rigid messenger

Rigidification
Methods - Introduce rings
NHMe

H
N

X
CH3

NHMe X
X

Introducing
rings
X

X
NHMe

NMe

OH
OH

OH
Rigidification

Rotatable
bonds
HN

CH3

HN

CH3

Me
N

Rigidification
Methods - Introduce rigid functional groups

Flexible chain

'locked' bonds

O
C

NH

Rigidification
Example
CO2H

Important
binding
groups

NH2
HN

Inhibits
platelet
aggregation

N
H
N

Guanidine Flexible chain

O
Ar

Diazepine ring system

NH2
CO2H

NH2
HN

HN

CO2H

N
H

N
N

CH3

Rigid

Rigid

O
Ar

Analogues

Rigid
Ar

Rigidification
Example - Combretastatin (anticancer agent)
Rotatable
bond
Z-isomer

H3CO

H3CO
OCH3

OCH3

OH

OH
OCH3

Combretastatin A-4
More active

H3CO

H3CO

H3CO

H3CO
OCH3

OH
OCH3

Combretastatin

OH

OCH3

E-isomer
Less active

Rigidification
Methods - Steric Blockers
X

Introduce
steric block

CH3

steric block

Flexible side chain

Y
X

Introduce
steric block

Steric
clash

Unfavourable conformation

Y
X

CH3

Coplanarity allowed

CH3

steric
clash

CH3

Orthogonal rings
preferred

Rigidification
Methods - Steric Blockers
H
N

H
N

O
N

CF3

Serotonin
antagonist

OMe

Introduce
methyl group
CH3

Steric
clash
H

H
N

O
N

CH3

CF3
OMe

Orthogonal ring

H
N

O
N

CF3
OMe

Increase in activity
Active conformation retained

Rigidification
Methods - Steric Blockers
Steric clash
freerotation

CF3O2SO

(CH2)4

Me
H

H
N
O

CF3O2SO

(CH 2)4

H
N
O

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