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.
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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.
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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