chapter 13 part 3 drug design optimizing target interactions

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