5- structure-activity relationships (sar). a structure-activity relationship (sar) is a statement of...

5- Structure-Activity Relationships (SAR).

A structure-activity relationship (SAR) is a statement of the effect of structure change on biological activity within a congeneric series (a family) of compounds.

– Methods of Studying Structure-Activity Relationships.

Both the affinity of a drug for its receptor and its intrinsic activity are determined by its chemical structure.

Several methods are presently used to study SAR.

Structure Activity Relationships (SAR)

• Alter, remove or mask a functional group• Test the analogue for activity• Conclusions depend on the method of testing

in vitro - tests for binding interactions with targetin vivo - tests for target binding interactions and/or

pharmacokinetics

• If in vitro activity drops, it implies group is important for binding

• If in vivo activity unaffected, it implies group is not important

AIM - Identify which functional groups are important for binding and/or activity

METHOD

NOTES ON ANALOGUES

• Modifications may disrupt binding by electronic / steric effects

• Easiest analogues to make are those made from lead compound

• Possible modifications may depend on other groups present

• Some analogues may have to be made by a full synthesis(e.g. replacing an aromatic ring with a cyclohexane ring)

• Allows identification of important groups involved in binding

• Allows identification of the pharmacophore

6. Identification of the active part:

Only a small part of the lead compound may be involved

in the appropriate receptor interactions. The relevant

groups on a molecule that interact with a receptor and

are responsible for the activity are collectively known as

the pharmacophore. The other atoms in the lead

molecule, referred to as auxophore.

PHARMACOPHORE

• Defines the important groups involved in binding

• Defines the relative positions of the binding groups

• Need to know Active Conformation

• Important to Drug Design

• Important to Drug Discovery

Auxophore

There are three types of auxophore:

Essential to maintain the integrity of the molecule and

hold the pharmacophoric groups in their appropriate

positions.

Interfere with the binding of the pharmacophore to the

receptor and need to be removed from the lead

compound

Some atoms of the auxophore may be dangling in

the space within the receptor and are neither binding

to the receptor nor preventing the pharmacophoric

atoms from binding. [these atoms can be modified

without loss of potency]. Also it can be modified to

solve pharmacokinetic problems [absorption,

distribution, metabolism, and excretion]

Pharmacophore

It is that portion of the molecule containing the essential organic functional groups that directly interact with the receptor active site and therefore confers upon the molecule the biologic activity of interest.

• Pharmacophoric descriptors are including : H-bond sites· Hydrophobic and electrostatic interaction sites

· Ring centers and virtual points

Distances, 3D relationship

COOH

H2N

p-aminobenzoic acid

pharmacophore

SNH2

OO

H2N

SNH

OO

H2N

N

O

CH3

SNH

OO

H2N

N

N

sulfanilamide sulfamethoxazole

sulfadiazine sulfisoxazole

Sulphonamides

SNH

OO

H2N

NO

CH3

CH3

Quinolones & fluoroquinolones

nalidixic acid

N

COOH

N

FO

HN

ciprofloxacin

N

COOH

N

FO

N OCH3H3C

ofloxacin

N

COOH

N

FO

OCH3

NH H

H

moxifloxacin

N N

COOH

O

C2H5

H3C

OH

NH3

+

OH

NH+H

CH3

OH

OH

L = lipophilic site; A = H-bond acceptor;D = H-bond donor; PD = protonated H-bond donor

DopaminePharmacophore

L

PD

D

d1

d2 d3

L

PD

D

d1

d2 d3

L

PD

D

d1

d2 d3

NH+

CO2H

CH3H

NH

L

PD

D

d1

d2 d3

C7OH

OH

A

D

B

C1

MeO OMe

ClClCl

BA

O

OC7OH

OHOH

A

B

C1

O

NMe2

OH

A B

CL

LL d1

d2

d3L

LL

d1

d2

d3

L

LL

d1

d2

d3

L

L

L

d1 d2

d3

L

LL

d1

d2

d3

"Pharmacophore"

Identification of the active part ( Pharmacophore)

• Simplification of the original lead compound is especially appropriate for polycyclic natural substances.

• In this process, systemic synthesis and evaluation of simpler analogues of the lead molecule is performed.

• Simplification of cocaine molecule led to introduction of many local anaesthetic drugs and discovery of benzoic acid ester moiety as a pharmacophore for such activity.

• The main result of this methodology is the identification of the pharmacophore group.

6.1 Structural (2D) Pharmacophore

Defines minimum skeleton connecting important binding groups

O

NMe

HO

HO

O

NMe

HO

HO

MORPHINE

O

NMe

HO

HO

MORPHINE

IMPORTANT GROUPS FOR ANALGESIC ACTIVITY

N

HO

ANALGESIC PHARMACOPHORE FOR OPIATES

MORPHINE

O

NMe

HO

HO

NMe

HO

LEVORPHANOL

NMe

HO

METAZOCINE

CH3

H3C

6.2 3D Pharmacophore

Defines relative positions in space of important binding groups

Example

N

HO

HO

N

x

x

O

NMe

HO

HO

O

N

Ar

O

N

Ar

11.3o

150o

18.5o

7.098 A

2.798 A

4.534 A

6.3 The Active Conformation

• Need to identify the active conformation in order to identify the 3D pharmacophore

• Conformational analysis - identifies possible conformations and their activities

• Conformational analysis is difficult for simple flexible molecules with large numbers of conformations

• Compare activity of rigid analogues

NH2HO HO NH2 HO

NH2

HO HO HO

I II

rotatable bonds

Dopamine

Locked bonds

6.4 Pharmacophores from Target Binding Sites

H-bonddonor oracceptor

aromaticcenter

basic orpositive

center

H-bonddonor oracceptor

aromaticcenter

basic orpositive center

Pharmacophore

OH

CO2

ASP

SER

PHE

Bindingsite

QSAR is mathematical relationships linking chemical structure and pharmacological activity in a quantitative manner for a series of compounds. Methods which can be used in QSAR include various regression and pattern recognition techniques.

Log1

Cæ è

ö ø

= 1.22 p - 1.59 s + 7.89

Conclusions:• Activity increases if p is + (i.e. hydrophobic substituents)• Activity increases if s is negative (i.e. e-donating substituents)

Examples: Adrenergic blocking activity of b-halo-b-arylamines

CH CH2 NRR'

XY

7 .DRUG DESIGN - OPTIMISING BINDING INTERACTIONS

AIM - To optimise binding interactions with target

• To increase activity and reduce dose levels• To increase selectivity and reduce side effects

STRATEGIES

REASONS

• The approaches for molecular modification can be classified as:

I. General approach

II. Special approach

1- Molecular disjunction (molecular dissociation,

dissection or simplification)

I. General approach

2 -Molecular conjunctive approachesAssociation of two or more molecules to give more complex analogues of the lead molecules with improved pharmacokinetic and pharmacodynamic properties represents typical process of conjunctive strategy.Molecular association processes comprise :-• Molecular addition• Molecular replication• Molecular hybridization

a. Molecular addition

• Molecular addition involves association of different molecules through weak forces such electrostatic attraction or hydrogen bonding.

• e.g. Electrostatic attraction in the urinary antiseptic methenamine mandelate.

b. Molecular replicationMolecular replication involves association of identical molecules through covalent bond formation (identical twin drug).

c. Molecular hybridizationMolecular hybridization involves association of two different molecules through covalent bond formation ( non identical twin drug).

II. Special approach1 .Variation of alkyl substituents.

2 .Extention of the structure.3 .Ring closure or ring opening

4 .Ring expansion and ring contraction5 .Homologation and chain branching6 .Introduction of unsaturation center

7 .Introduction, removal or replacement of bulkygroups

8 .Introduction of chiral center9 .Conformation restriction (molecular rigidification)

10 .Isosteres and bioisosteres

1 . 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 : Vary length and bulk of alkyl group to introduce selectivity

1 .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

1 . Vary Alkyl Substituents

Example: Selectivity of adrenergic agonists and antagonists for b-adrenoceptors over a-adrenoceptors

Salbutamol (Ventolin )(Anti-asthmatic)

Adrenaline

Propranolol(b-Blocker)


OH

O NH

CH3

CH3H

HOCH2

HO

HN

CCH3

OH

CH3

H

CH3

HO

HO

HN

CH3

OHH

a-Adrenoceptor

H-Bondingregion

H-Bondingregion

H-Bondingregion

Van der Waalsbonding region

Ionicbonding

region

ADRENALINE

a-Adrenoceptor

a-Adrenoceptor

b-Adrenoceptor

ADRENALINE

SALBUTAMOL

b-Adrenoceptor

b-Adrenoceptor

a-Adrenoceptor

SALBUTAMOL

SALBUTAMOL

a-Adrenoceptor

a-Adrenoceptor


Notes on synthetic feasibility of analogues

• Feasible to remove alkyl substituents on heteroatomsand replace with other alkyl substituents

• Difficult to modify alkyl substituents on the carbon skeleton of a lead compound. Full synthesis is usually required

Binding Region(H-Bond)

Binding Region(for Y)

para Substitution

Bindingsite

HO

Y

meta Substitution

Bindingsite

O

H

Y

2 .Vary Aryl Substituents • Vary substituents • Vary substitution pattern

WeakH-Bond

StrongH-Bond

(increasedactivity)

2 .Vary Aryl Substituents

Anti-arrhythmic activity best when substituent is at 7-position

Vary substitution pattern to enhance binding interactions

Benzopyrans

6

7

8O

O

NR

MeSO2NH

2 .Vary Aryl Substituents Vary substitution pattern to enhance binding strength indirectly- electronic effects

Binding strength of NH2 as HBD affected by relative position of NO2

Stronger when NO2 is at para position

..

Meta )Inductive electron withdrawing effect(

N

O

O

NH2

..

Para )Electron withdrawing effect due to resonance and inductive effects leading to a weaker base(

NO

NH2

ON

O

NH2

O

RECEPTOR

Rationale : To explore target binding site for further bindingregions to achieve additional binding interactions

3 .Extension - Extra Functional Groups

Unusedbinding

regionDRUG

RECEPTOR

DRUGExtra

functionalgroup

Binding regions

Binding group

DrugExtension

Example : ACE Inhibitors

3 .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: Second-generation anti-impotence drugs

Extension - extra functional groups

Notes:• Extension - addition of pyridine ring•Increased target selectivity

ViagraN

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

Rationale : • Useful if a chain is present connecting two binding groups• Vary length of chain to optimise interactions

Chain Extension / Contraction

RECEPTOR

A BA B

RECEPTOR

Binding regions

Binding groupsA & B

Weakinteraction

Stronginteraction

Chain extension

Bindinggroup

Bindinggroup

Example : N-Phenethylmorphine

Chain Extension / Contraction

Optimum chain length = 2

HO

O

HO

N (CH2)n

H

4- Homologation

A homologous series is a group of compounds thatdiffer by a constant unit, generally a CH2 group

e.g., alkyltrimethylammonium analogs possess different types of activity depending on the length of alkyl group:

n= 5 muscarinic agonists n= 6 or 7 partial agonists n= 8 or more muscarinic antagonists.

H3C N

CH3

CH3

(CH2)n CH3

Cl

A homologous series is a series of analogs that differ in structure by simple increment in molecular formula.

These may produced by sequential chemical changes which includes increasing or decreasing the length of a carbon chain.

Rationale : To improve overlap of binding groups with their binding regions

5 .Ring Expansion / Contraction

Hydrophobic regions

R R RR

Ringexpansion

Example

5 .Ring Expansion / Contraction

Binding regions

Binding site Binding site

Vary nto vary

ring size

NH

)CH2(n

N

N

CO2O

O2C

Ph

N

N

CO2ONH

Ph

O2CNH

N

N

CO2O

O2C

Ph

I

NN

CO2Et

CH3

CO2Et

H3C

MepridineEthoheptazine

N

N

O

O

R1

R2

O

H

H

N

N

O

O

R1

R2

H

H

BarbituratesHydantoins

Ring Enlargement and Ring Contraction:

Rationale : • Replace aromatic/heterocyclic rings with other ring systems• Often done for patent reasons

6 . 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

N

N

Rationale : Sometimes results in improved properties

6 . Ring Variations

Example :

Improved selectivityvs. fungal enzyme

Antifungal agent

Cl

F

C

OHN

N

Structure I

Ringvariation

Cl

F

C

OHN

NN

UK-46245

Example - Nevirapine )antiviral agent(

6 .Ring Variations

N

HN

N

O

CO2tBu

Lead compound

N

HN

N N

O

CO2tBu

N

HN

N N

OMe

Nevirapine

Additionalbinding group

7-Introduction, removal or replacement of bulky groups

• This special process is used mainly to:• Convert agonist to antagonist or• Prevent the enzymatic degradation

Example for preventing enzymatic degradation;

β-lactamase resistant penicillins

Bulky group introduced near the ring prevent enzymatic

degradation by …..

N

S

OOCH3

OCH3

O

CH3

CH3

COOH

Methicillin

N

HN

N

HN

N

HNN

HN S NH

HN

N

N

Tolazoline Adrenergic antagonist

Naphazoline Adrenergic agonist

CimetidineH2 receptor antagonist

4-MethylhistamineH2 receptor agonist

Introduction, Removal, or Replacement of Bulky groups:

O

N

O

N

HO

HO H

HO

OH

NefopamDiphenhydramine

Estradiol DES

8 .Ring Closure and Opening:

9 -Introduction of chiral centers

• Receptors are chiral entities and the interactions of many drugs at specific sites are chirality type of interaction.

• E.g. The simple addition of α-methyl group to give ACE inhibitor captopril increased by 10-folds over the des-methyl compound.