Transcript No Slide Title

Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 13
QUANTITATIVE STRUCTUREACTIVITY RELATIONSHIPS (QSAR)
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Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Introduction
Hydrophobicity of the Molecule (4 slides)
Hydrophobicity of Substituents (2 slides)
Electronic Effects
4.1.
Hammett Substituent Constant (s) (7 slides)
4.2.
Electronic Factors R & F
4.3.
Aliphatic electronic substituents
Steric Factors (3 slides)
Hansch Equation (4 slides)
Craig Plot (2 slides)
Topliss Scheme (5 slides)
Bio-isosteres
Free-Wilson Approach (3 slides)
Case Study (10 slides)
3D-QSAR (10 slides)
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
in octanol]
Partition Coefficient P = [Drug
[Drug in water]
High P
High hydrophobicity
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2. Hydrophobicity of the Molecule
•
Activity of drugs is often related to P
e.g. binding of drugs to serum albumin
(straight line - limited range of log P)
Log (1/C)
.
.
.
.
.
.
.. .
0.78
•
•
3.82
Log1C = 0.75 logP + 2.30
Log P
Binding increases as log P increases
Binding is greater for hydrophobic drugs
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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
Optimum value of log P for anaesthetic activity = log Po
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2. Hydrophobicity of the Molecule
•
QSAR equations are only applicable to compounds in the
same structural class (e.g. ethers)
•
However, log Po is similar for anaesthetics of different
structural classes (ca. 2.3)
•
Structures with log P ca. 2.3 enter the CNS easily
(e.g. potent barbiturates have a log P of approximately 2.0)
•
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 :
Benzene
(Log P = 2.13)
Chlorobenzene
(Log P = 2.84)
pCl = 0.71
•
•
Benzamide
(Log P = 0.64)
pCONH 2 = -1.49
Positive values imply substituents are more hydrophobic than H
Negative values imply substituents are less
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hydrophobic than H
3. Hydrophobicity of Substituents
- the substituent hydrophobicity constant (p)
•
•
The value of p is only valid for parent structures
It is possible to calculate log P using p values
Example :
Cl
Log P(theory)
CONH2
meta-Chlorobenzamide
•
•
•
Log P (observed)
= log P(benzene) + pCl + pCONH2
= 2.13 + 0.71 - 1.49
= 1.35
= 1.51
A QSAR equation may include both P and p.
P measures the importance of a molecule’s overall
hydrophobicity (relevant to absorption, binding etc)
p identifies specific regions of the molecule which might
interact with hydrophobic regions in the binding site
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4. Electronic Effects
4.1 Hammett Substituent Constant (s)
•
•
The constant (s) a measure of the e-withdrawing or edonating influence of substituents
It can be measured experimentally and tabulated
(e.g. s for aromatic substituents is measured by comparing the
dissociation constants of substituted benzoic acids with benzoic acid)
X
X
CO2H
X=H
CO2
+
H
[PhCO
2-]
KH = Dissociation constant=
[PhCO2H]
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4.1 Hammett Substituent Constant (s)
X= electron withdrawing group (e.g. NO2)
X = e le ctron
withdrawing X
group
X
CO2H
CO2
+
H
Charge is stabilised by X
Equilibrium shifts to right
KX > K H
s
X
= log
KX
= logKX - logKH
KH
Positive value
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4.1 Hammett Substituent Constant (s)
X= electron donating group (e.g. CH3)
X = e le ctron
withdrawing X
group
X
CO2H
CO2
+
H
Charge destabilised
Equilibrium shifts to left
KX < K H
s
X
= log
KX
= logKX - logKH
KH
Negative value
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4.1 Hammett Substituent Constant (s)
s value depends on inductive and resonance effects
s value depends on whether the substituent is meta or para
ortho values are invalid due to steric factors
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4.1 Hammett Substituent Constant (s)
sm (NO2) =0.71
sp (NO2) =0.78
EXAMPLES:
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
DRUG
DRUG
DRUG
DRUG
e-withdrawing
(inductive +
resonance effects)
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4.1 Hammett Substituent Constant (s)
sm (OH) =0.12
EXAMPLES:
sp (OH) =-0.37
meta-Substitution
OH
e-withdrawing (inductive effect only)
DRUG
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:
O
O
P
OEt
X
OEt
log1C= 2.282s - 0.348
Diethylphenylphosphates
(Insecticides)
Conclusion : e-withdrawing substituents increase activity
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4.2 Electronic Factors R & F
•
R - Quantifies a substituent’s resonance effects
•
F - Quantifies a substituent’s inductive effects
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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
Hydrol ysi s
C
X
CH2
+
C
OMe
X
CH2
HOMe
OH
X= electron donating
Rate
sI = -ve
X= electron withdrawing
Rate
sI = +ve
Basic conditions:
Acidic conditions:
Rate affected by steric + electronic factors
Gives sI after correction for steric effect
Rate affected by steric factors only (see Es)
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5. Steric Factors
Taft’s Steric Factor (Es)
•
Measured by comparing the rates of hydrolysis of substituted
aliphatic esters against a standard ester under acidic
conditions
Es = log kx - log ko
kx represents the rate of hydrolysis of a substituted ester
ko represents the rate of hydrolysis of the parent ester
•
•
•
Limited to substituents which interact sterically with the
tetrahedral transition state for the reaction
Cannot be used for substituents which interact with the
transition state by resonance or hydrogen bonding
May undervalue the steric effect of groups in an
intermolecular process (i.e. a drug binding to a receptor)
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5. Steric Factors
Molar Refractivity (MR) - a measure of a substituent’s volume
MR =
(n 2 - 1)
(n 2 - 2)
x
mol. wt.
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
Example - Carboxylic acid
B4
O
B
B3
3
B2
C
H
O
B
O
C
O
B1
4
H
L
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6. Hansch Equation
•
A QSAR equation relating various physicochemical properties
to the biological activity of a series of compounds
•
Usually includes log P, electronic and steric factors
•
Start with simple equations and elaborate as more structures
are synthesised
•
Typical equation for a wide range of log P is parabolic
Log1C = - k1(logP)2 + k 2 logP + k 3 s + k 4 Es + k 5
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6. Hansch Equation
Example: Adrenergic blocking activity of b-halo-b-arylamines
Y
X
CH CH2
1 

Log C =
NRR'
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
X
Y
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:
•
•
•
A range of values for each physicochemical property studied
values must not be correlated for different properties (i.e. they
must be orthogonal in value)
at least 5 structures are required for each parameter studied
Substituent H
Me Et n-Pr
p
0.00 0.56 1.02 1.50
MR
0.10 0.56 1.03 1.55
Substituent H
Me OMe
p
0.00 0.56 -0.02
MR
0.10 0.56 0.79
n-Bu
2.13
1.96
Correlated values.
Are any differences
due to p or MR?
NHCONH2 I
CN
-1.30
1.12 -0.57
1.37
1.39 0.63
No correlation in values
Valid for analysing effects
of p and MR.
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7. Craig Plot
Craig plot shows values for 2 different physicochemical properties
for various substituents
Example:
.
.
. . . ..
. .
.
.
. ..
.
.
.
.
.
.
.
.
.
+
1.0
+s -p
CF3SO 2
.75
CN
CH3SO2
SO 2NH2
NO2
.50
OCF3
.25
CO2H
-2.0
-p
-1.6
-1.2
-.8
-.4
SF5
CF3
CH3CO
CONH2
+s +p
F
.4
I
Br
Cl
.8
1.2
1.6
2.0
+p
CH3CONH
-.25
Et
t-Butyl
OCH3
OH
Me
-.50
NMe 2
NH2
-.75
-s -p
-1.0
-
-s +p
©1
7. Craig Plot
•
Allows an easy identification of suitable substituents for a
QSAR analysis which includes both relevant properties
•
Choose a substituent from each quadrant to ensure
orthogonality
•
Choose substituents with a range of values for each property
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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
4-OMe
L
M
E
E
4-CH3
L
M
E
M
3,4-Cl2
L
E
4-But
3-Cl
3-Cl
L
E
M
M
3-CF3-4-Cl
4-CF3
3-CF3-4-NO2
2,4-Cl2
3-NMe2
S e e C e ntral
Branch
L
4-NMe2
E
3-CH3
2-Cl
M
3-Me-4-NMe2
4-NO2
3-CF3
4-NO2
3,5-Cl2
3-NO2
4-F
4-NH2
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8. Topliss Scheme
Rationale
Replace H with
para-Cl (+p and +s)
Act.
+p and/or +s
advantageous
add second Cl to
increase p and s
further
Little
change
favourable p
unfavourable s
replace with Me
(+p and -s)
Act.
+p and/or +s
disadvantageous
replace with OMe
(-p and -s)
Further changes suggested based on arguments of p,s and
steric strain
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8. Topliss Scheme
Aliphatic substituents
CH3
L
E
H; CH2OCH3 ; CH2SO2CH3
i-Pr
M
Et
L
E
L
M
Cyclopentyl
E
END
CHCl2 ; CF3 ; CH2CF3 ; CH2SCH3
Ph ; CH2Ph
M
Cyclohexyl
Cyclobutyl; cyclopropyl
t-Bu
CH2Ph
CH2CH2Ph
©1
8. Topliss Scheme
Example
O rde r of
S ynth e sis
SO2NH2
R
1
2
3
4
5
R
H
4-C l
3,4-Cl2
4-Br
4-NO2
Bi ol ogical Hi gh
Acti vi ty
Pote n cy
M
L
E
M
*
M= More Activity
L= Le ss Acti vi ty
E = Equ al Acti vi ty
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8. Topliss Scheme
Example
R
N
N
N
N
O rde r of
S ynth e si s
CH2CH2CO2H
1
2
3
4
5
6
7
8
R
H
4-C l
4-Me O
3-C l
3-C F3
3-Br
3-I
3,5-C 2l
Bi ol ogi cal Hi gh
Acti vi ty
Pote n cy
L
L
M
L
M
L
M
*
*
*
M= More Acti vi ty
L= Le ss Activity
E = Equ al Acti vi ty
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9. Bio-isosteres
NC
C
O
Substitue nt
p
sp
sm
MR
•
•
C
-0.55
0.50
0.38
11.2
CN
C
CH3
O
CH3
0.40
0.84
0.66
21.5
S
CH3
-1.58
0.49
0.52
13.7
O
O
O
S CH3
S NHCH3
C NMe2
O
O
-1.63
0.72
0.60
13.5
-1.82
0.57
0.46
16.9
-1.51
0.36
0.35
19.2
Choose substituents with similar physicochemical properties
(e.g. CN, NO2 and COMe could be bio-isosteres)
Choose bio-isosteres based on most important
physicochemical property
(e.g. COMe & SOMe are similar in sp; SOMe and SO2Me are similar in
p)
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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
•
•
•
Xn is an indicator variable which is given the value 0 or 1
depending on whether the substituent (n) is present or not
The contribution of each substituent (n) to activity is
determined by the value of kn
Z is a constant representing the overall activity of the
structures studied
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10. Free-Wilson Approach
Advantages
•
•
•
No need for physicochemical constants or tables
Useful for structures with unusual substituents
Useful for quantifying the biological effects of molecular
features that cannot be quantified or tabulated by the
Hansch method
Disadvantages
•
•
•
A large number of analogues need to be synthesised to
represent each different substituent and each different
position of a substituent
It is difficult to rationalise why specific substituents are
good or bad for activity
The effects of different substituents may not be additive
(e.g. intramolecular interactions)
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10. Free-Wilson / Hansch Approach
Advantages
•
It is possible to use indicator variables as part of a Hansch
equation - see following Case Study
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11. Case Study
QSAR analysis of pyranenamines (SK & F)
(Anti-allergy compounds)
O
OH
OH
X
3
Y
4
NH
O
O
O
5
Z
©1
O
OH
OH
11. Case Study
3
Y
4
NH
O
Stage 1
X
O
O
19 structures were synthesised to study p and s
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 sis +ve or -ve)
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5
Z
O
OH
OH
11. Case Study
X
3
Y
4
NH
O
O
O
5
Stage 2 61 structures were synthesised, concentrating on
hydrophilic substituents to test the first equation
Anomalies
a) 3-NHCOMe, 3-NHCOEt, 3-NHCOPr.
Activity should drop as alkyl group becomes bigger and more
hydrophobic, but the activity is similar for all three substituents
b) OH, SH, NH2 and NHCOR at position 5 : Activity is greater than expected
c) NHSO2R : Activity is worse than expected
d) 3,5-(CF3)2 and 3,5(NHMe)2 : Activity is greater than expected
e) 4-Acyloxy : Activity is 5 x greater than expected
©1
Z
O
OH
OH
11. Case Study
Theories
X
3
Y
4
NH
O
O
O
5
a) 3-NHCOMe, 3-NHCOEt, 3-NHCOPr.
Possible steric factor at work. Increasing the size of R may be good for activity
and balances out the detrimental effect of increasing hydrophobicity
b) OH, SH, NH2, and NHCOR at position 5
Possibly involved in H-bonding
c) NHSO2R
Exception to H-bonding theory - perhaps bad for steric or electronic reasons
d) 3,5-(CF3)2 and 3,5-(NHMe)2
The only disubstituted structures where a substituent at position 5 was electron
withdrawing
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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Z
O
OH
OH
11. Case Study
X
3
Y
4
NH
O
O
O
5
Z
Stage 3 Alter the QSAR equation to take account of new results
1
Log C = -0.30Sp - 1.35(Ss )2 + 2.0(F-5) + 0.39(345-HBD) -0.63(NHSO2 )
+0.78(M-V) + 0.72(4-OCO) - 0.75
Conclusions
(F-5)
(3,4,5-HBD)
(NHSO2)
(M-V)
4-O-CO
e-withdrawing group at position 5 increases activity
(based on only 2 compounds though)
H-bond donor group at positions 3, 4,or 5 is good for activity
Term = 1 if a HBD group is at any of these positions
Term = 2 if HBD groups are at two of these positions
Term = 0 if no HBD group is present at these positions
Each HBD group increases activity by 0.39
Equals 1 if NHSO2 is present (bad for activity by -0.63).
Equals zero if group is absent.
Volume of any meta substituent. Large substituents at meta
position increase activity
Equals 1 if acyloxy group is present (activity increases by 0.72).
Equals 0 if group absent
©1
O
OH
OH
11. Case Study
X
3
Y
4
NH
O
O
O
5
Z
Stage 3 Alter the QSAR equation to take account of new results
1
Log C = -0.30Sp - 1.35(Ss )2 + 2.0(F-5) + 0.39(345-HBD) -0.63(NHSO2 )
+0.78(M-V) + 0.72(4-OCO) - 0.75
The terms (3,4,5-HBD), (NHSO2), and 4-O-CO are examples of indicator
variables used in the free-Wilson approach and included in a Hansch equation
©1
O
OH
OH
11. Case Study
X
3
Y
4
NH
O
O
O
5
Z
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
©1
O
OH
OH
11. Case Study
3
Y
4
NH
O
Stage 5
X
O
O
5
Z
Revise Equation
1
Log C = -0.034(Sp )2 -0.33Sp + 4.3(F-5) + 1.3 (R-5) - 1.7(Ss )2 + 0.73(345- HBD)
- 0.86 (HB-INTRA) - 0.69(NHSO2) + 0.72(4-OCO) - 0.59
a) Increasing the hydrophilicity of substituents allows the identification of an
optimum value for p (Sp = -5). The equation is now parabolic (-0.034 (Sp)2)
b) The optimum value of Sp is very low and implies a hydrophilic binding site
c) R-5 implies that resonance effects are important at position 5
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
e) The steric parameter is no longer significant and is not present
©1
11. Case Study
Stage 6
Optimum Structure and binding theory
XH
X
O
OH
NH
C
CH
CH2 OH
NH
C
CH
CH2 OH
O
OH
X
3
RHN
5
X
NH3
©1
11. Case Study
NOTES on the optimum structure
•
It has unusual NHCOCH(OH)CH2OH groups at positions 3 and
5
•
It is 1000 times more active than the lead compound
•
The substituents at positions 3 and 5
• are highly polar,
• are capable of H-bonding,
• are at the meta positions and are not ortho to each other
• allow a favourable F-5 parameter for the substituent at
position 5
•
The structure has a negligible (Ss)2 value
©1
12. 3D-QSAR
•
•
•
•
•
•
Physical properties are measured for the molecule as a whole
Properties are calculated using computer software
No experimental constants or measurements are involved
Properties are known as ‘Fields’
Steric field - defines the size and shape of the molecule
Electrostatic field - defines electron rich/poor regions of
molecule
• Hydrophobic properties are relatively unimportant
Advantages over QSAR
• No reliance on experimental values
• Can be applied to molecules with unusual substituents
• Not restricted to molecules of the same structural class
• Predictive capability
©1
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
©1
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
©1
12. 3D-QSAR
Method
•
Place the pharmacophore into a lattice of grid points
.
.
.
.
.
Grid points
•
Each grid point defines a point in space
©1
12. 3D-QSAR
Method
•
Position molecule to match the pharmacophore
.
.
.
.
.
Grid points
•
Each grid point defines a point in space
©1
12. 3D-QSAR
Method
•
A probe atom is placed at each grid point in turn
.
.
•
.
Probe atom
.
.
Probe atom = a proton or sp3 hybridised carbocation
©1
12. 3D-QSAR
Method
•
A probe atom is placed at each grid point in turn
.
.
•
.
Probe atom
.
.
Measure the steric or electrostatic interaction of the probe
atom with the molecule at each grid point
©1
12. 3D-QSAR
Method
•
•
•
•
•
•
•
•
The closer the probe atom to the molecule, the higher the steric
energy
Can define the shape of the molecule by identifying grid points of
equal steric energy (contour line)
Favourable electrostatic interactions with the positively charged
probe indicate molecular regions which are negative in nature
Unfavourable electrostatic interactions with the positively charged
probe indicate molecular regions which are positive in nature
Can define electrostatic fields by identifying grid points of equal
energy (contour line)
Repeat the procedure for each molecule in turn
Compare the fields of each molecule with their biological activity
Can then identify steric and electrostatic fields which are favourable
or unfavourable for activity
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12. 3D-QSAR
Method
.
. . ..
Tabulate fields for each
compound at each grid point
Compound Biological Steric fields (S)
Electrostatic fields (E)
activity
at grid points (001-998)
at grid points (001-098)
S001 S002 S003 S004 S005 etc E001 E002 E003 E004 E005 etc
1
5.1
2
6.8
3
5.3
4
6.4
5
6.1
Partial least squares
analysis (PLS)
QSAR equation
Activity = aS001 + bS002 +……..mS998 + nE001 +…….+yE998 + z
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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
N
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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
NH
positions 6 and 7
9
2
R1
7
R2
6
N
Substituents: CH3, Cl, NO2, OCH3, NH2, F
(Spread of values with no correlation)
1
1 2
1
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
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13. 3D-QSAR - CASE STUDY
CoMFA Study
Analysis includes tetracyclic anticholinesterase inhibitors (II)
NH2
R1
8
R3
1
R2
2
N
7
R4
3
II
•
•
R5
Not possible to include above structures in a conventional
QSAR analysis since they are a different structural class
Molecules belonging to different structural classes must be
aligned properly according to a shared pharmacophore
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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
7
6
•
•
Blue areas - addition of steric bulk increases activity
Red areas - addition of steric bulk decreases activity
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13. 3D-QSAR - CASE STUDY
Prediction
6-Bromo analogue of tacrine predicted to be active (pIC50 = 7.40)
Actual pIC50 = 7.18
NH2
Br
N
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