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Patrick ch13
Patrick ch13
Chapter 13
QUANTITATIVE STRUCTURE-
ACTIVITY RELATIONSHIPS (QSAR)
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Contents
1. Introduction
2. Hydrophobicity of the Molecule (4 slides)
3. Hydrophobicity of Substituents (2 slides)
4. Electronic Effects
4.1. Hammett Substituent Constant (s) (7 slides)
4.2. Electronic Factors R & F
4.3. Aliphatic electronic substituents
5. Steric Factors (3 slides)
6. Hansch Equation (4 slides)
7. Craig Plot (2 slides)
8. Topliss Scheme (5 slides)
9. Bio-isosteres
10. Free-Wilson Approach (3 slides)
11. Case Study (10 slides)
12. 3D-QSAR (10 slides)
13. 3D-QSAR Case Study(7 slides)
[62 slides]
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1. Introduction
• Aims
• To relate the biological activity of a series of compounds to
their physicochemical parameters in a quantitative fashion
using a mathematical formula
• Requirements
• Quantitative measurements for biological and
physicochemical properties
• Physicochemical Properties
• Hydrophobicity of the molecule
• Hydrophobicity of substituents Most common
• Electronic properties of substituents properties studied
• Steric properties of substituents
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2. Hydrophobicity of the Molecule
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2. Hydrophobicity of the Molecule
Log (1/C)
. . .
.
.. . . . Log1C = 0.75 logP + 2.30
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2. Hydrophobicity of the Molecule
Example 2 General anaesthetic activity of ethers
(parabolic curve - larger range of log P values)
Log (1/C)
1
Log C = - 0.22(logP)2 + 1.04 logP + 2.16
o
Log P Log P
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2. Hydrophobicity of the Molecule
• Can alter log P value of drugs away from 2.0 to avoid CNS
side effects
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3. Hydrophobicity of Substituents
- the substituent hydrophobicity constant (p)
• A measure of a substituent’s hydrophobicity relative to
hydrogen
• Tabulated values exist for aliphatic and aromatic substituents
• Measured experimentally by comparison of log P’s with parent
structure
Cl CONH2
Example :
Example : Cl
X X
CO2H CO2 + H
[PhCO 2-]
X=H KH = Dissociation constant=
[PhCO2H]
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4.1 Hammett Substituent Constant (s)
X = electron
withdrawing X X
group CO2H CO2 + H
Charge is stabilised by X
Equilibrium shifts to right
KX > KH
KX
s X = log = logKX - logKH
KH
Positive value
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4.1 Hammett Substituent Constant (s)
X= electron donating group (e.g. CH3)
X = electron
withdrawing X X
group CO2H CO2 + H
Charge destabilised
Equilibrium shifts to left
KX < KH
KX
s X = log = logKX - logKH
KH
Negative value
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4.1 Hammett Substituent Constant (s)
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4.1 Hammett Substituent Constant (s)
meta-Substitution
O
N
O e-withdrawing (inductive effect only)
DRUG
para-Substitution
O O O O O O O O
N N N N
e-withdrawing
(inductive +
resonance effects)
DRUG DRUG DRUG DRUG
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4.1 Hammett Substituent Constant (s)
meta-Substitution
OH
para-Substitution
OH OH OH OH
e-donating by resonance
more important than
inductive effect
DRUG DRUG DRUG DRUG
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4.1 Hammett Substituent Constant (s)
QSAR Equation:
X
O P OEt
log1C= 2.282s - 0.348
OEt
Diethylphenylphosphates
(Insecticides)
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4.2 Electronic Factors R & F
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4.3 Aliphatic electronic substituents
• Defined by sI
• Purely inductive effects
• Obtained experimentally by measuring the rates of hydrolyses
of aliphatic esters
• Hydrolysis rates measured under basic and acidic conditions
O O
Hydrolysis
C C + HOMe
X CH2 OMe X CH2 OH
(n 2 - 1) mol. wt.
MR = x
(n 2 - 2) density
Correction factor Defines volume
for polarisation
(n=index of
refraction)
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5. Steric Factors
Verloop Steric Parameter
- calculated by software (STERIMOL)
- gives dimensions of a substituent
- can be used for any substituent
O B
3
B2
C
H O C O B1
O B
4
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6. Hansch Equation
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6. Hansch Equation
Example: Adrenergic blocking activity of b-halo-b-arylamines
Y X
CH CH2 NRR'
1
Log C = 1.22 p - 1.59 s + 7.89
Conclusions:
• Activity increases if p is +ve (i.e. hydrophobic substituents)
• Activity increases if s is negative (i.e. e-donating substituents)
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6. Hansch Equation
Example: Antimalarial activity of phenanthrene aminocarbinols
CH2NHR'R"
(HO)HC
1
Log C = -0.015 (logP)2 + 0.14 logP + 0.27 SpX + 0.40 SpY + 0.65 SsX + 0.88 SsY + 2.34
Conclusions:
• Activity increases slightly as log P (hydrophobicity) increases
(note that the constant is only 0.14)
• Parabolic equation implies an optimum log Po value for activity
• Activity increases for hydrophobic substituents (esp. ring Y)
• Activity increases for e-withdrawing substituents (esp. ring Y)
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6. Hansch Equation
Choosing suitable substituents
Substituents must be chosen to satisfy the following criteria:
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7. Craig Plot
Craig plot shows values for 2 different physicochemical properties
for various substituents
Example: +s -p
. . + 1.0
+s +p
. . . .. . .
CF3SO 2
.75
NO2
.
CN SF5
CH3SO2 .50
. ..
SO 2NH2 CF3
.
CH3CO
CONH2
OCF3
.
.25
I
.
CO2H Cl Br
.
-.8 -.4 .4
.
-2.0 -1.6 -1.2 F .8 1.2 1.6 2.0
-p
. .
CH3CONH +p
. OCH3
-.25 Me Et
t-Butyl
. .
OH
-.50
NH2 NMe 2
-.75
-s -p -1.0 -s +p
-
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7. Craig Plot
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8. Topliss Scheme
Used to decide which substituents to use if optimising compounds
one by one (where synthesis is complex and slow)
Example: Aromatic substituents
H
4-Cl
L E M
4-OMe 4-CH3 3,4-Cl2
L E M L E M L E M
4-But 3-CF3-4-Cl
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8. Topliss Scheme
Rationale
Replace H with
para-Cl (+p and +s)
Act. Little Act.
change
add second Cl to
replace with OMe
increase p and s replace with Me
(-p and -s)
further (+p and -s)
CH3
i-Pr
L E M
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8. Topliss Scheme
Example
SO2NH2 1 H -
R 2 4-Cl M
3 3,4-Cl2 L
4 4-Br E
5 4-NO2 M *
M= More Activity
L= Less Activity
E = Equal Activity
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8. Topliss Scheme
Example
R 1 H -
N N L
2 4-Cl
CH2CH2CO2H 3 4-MeO L
4 3-Cl M *
5 3-CF 3 L
6 3-Br M *
7 3-I L
8 3,5-Cl 2 M *
M= More Activity
L= Less Activity
E = Equal Activity
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9. Bio-isosteres
NC CN
O C O O O O
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10. Free-Wilson Approach
Method
• The biological activity of the parent structure is measured
and compared with the activity of analogues bearing
different substituents
• An equation is derived relating biological activity to the
presence or absence of particular substituents
Activity = k1X1 + k2X2 +.…knXn + Z
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11. Case Study
QSAR analysis of pyranenamines (SK & F)
(Anti-allergy compounds)
O OH OH X
3
Y
NH 4
Z
5
O O O
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O OH OH X
3
11. Case Study NH
Y
4
Z
5
O O O
1
Log C = -0.14Sp - 1.35(Ss )2 - 0.72
Sp and Ss = total values for p and s for all substituents
Conclusions:
• Activity drops as p increases
• Hydrophobic substituents are bad for activity - unusual
• Any value of s results in a drop in activity
• Substituents should not be e-donating or e-withdrawing
(activity falls if sis +ve or -ve)
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O OH OH X
3
11. Case Study NH
Y
4
Z
5
O O O
b) OH, SH, NH2 and NHCOR at position 5 : Activity is greater than expected
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O OH OH X
3
11. Case Study NH
Y
4
Theories O O O
5
Z
c) NHSO2R
Exception to H-bonding theory - perhaps bad for steric or electronic reasons
e) 4-Acyloxy
Presumably acts as a prodrug allowing easier crossing of cell membranes.
The group is hydrolysed once across the membrane.
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O OH OH X
3
11. Case Study NH
Y
4
Z
5
O O O
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O OH OH X
3
11. Case Study NH
Y
4
Z
5
O O O
Stage 4
37 Structures were synthesised to test steric and F-5 parameters,
as well as the effects of hydrophilic, H-bonding groups
Anomalies
Two H-bonding groups are bad if they are ortho to each other
Explanation
Possibly groups at the ortho position bond with each other rather
than with the receptor - an intramolecular interaction
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O OH OH X
3
11. Case Study NH
Y
4
Z
5
O O O
b) The optimum value of Sp is very low and implies a hydrophilic binding site
d) HB-INTRA equals 1 for H-bonding groups ortho to each other (act. drops -086)
equals 0 if H-bonding groups are not ortho to each other
XH X
O OH
X
NH C CH CH2 OH
3
RHN
5
NH C CH CH2 OH X
O OH
NH3
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11. Case Study
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12. 3D-QSAR
Method
• Comparative molecular field analysis (CoMFA) - Tripos
• Build each molecule using modelling software
• Identify the active conformation for each molecule
• Identify the pharmacophore
OH
HO NHCH3
HO
Build 3D
model
Active conformation Define pharmacophore
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12. 3D-QSAR
Method
• Comparative molecular field analysis (CoMFA) - Tripos
• Build each molecule using modelling software
• Identify the active conformation for each molecule
• Identify the pharmacophore
OH
HO NHCH3
HO
Build 3D
model
Active conformation Define pharmacophore
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12. 3D-QSAR
Method
• Place the pharmacophore into a lattice of grid points
.
.
. .
.
Grid points
.
.
. .
.
Grid points
.
. Probe atom
. .
.
.
. Probe atom
. .
.
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12. 3D-QSAR
Method
.
. . ..
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12. 3D-QSAR
Method
• Define fields using contour maps round a representative
molecule
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13. 3D-QSAR - CASE STUDY
Tacrine
Anticholinesterase used in the treatment of Alzheimer’s disease
NH2
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13. 3D-QSAR - CASE STUDY
Conventional QSAR Study
12 analogues were synthesised to relate their activity with the
hydrophobic, steric and electronic properties of substituents at
positions 6 and 7 9
NH 2
R1 7
R2 6 N
1 1 1 2
Log C = pIC50 = -3.09 MR(R ) + 1.43F(R ,R ) + 7.00
Conclusions
• Large groups at position 7 are detrimental
• Groups at positions 6 & 7 should be electron withdrawing
• No hydrophobic effect ©1
13. 3D-QSAR - CASE STUDY
CoMFA Study
Analysis includes tetracyclic anticholinesterase inhibitors (II)
NH2
R1 8 R3
1
2
R2 7 N R4
3
II R5
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13. 3D-QSAR - CASE STUDY
Possible Alignment
Good overlay but assumes similar binding modes
Overlay
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13. 3D-QSAR - CASE STUDY
X-Ray Crystallography
• A tacrine / enzyme complex was crystallised and analysed
• Results revealed the mode of binding for tacrine
• Molecular modelling was used to modify tacrine to structure
(II) whilst still bound to the binding site (in silico)
• The complex was minimised to find the most stable binding
mode for structure II
• The binding mode for (II) proved to be different from tacrine
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13. 3D-QSAR - CASE STUDY
Alignment
• Analogues of each type of structure were aligned according to
the parent structure
• Analysis shows the steric factor is solely responsible for
activity
NH2
Br N
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