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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
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)
1 .Vary Alkyl Substituents
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
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
SALBUTAMOL
a-Adrenoceptor
a-Adrenoceptor
1 .Vary Alkyl Substituents
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.