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3D-QSAR

Notes

sical properties are measured for the molecule as a whole


perties are calculated using computer software
experimental constants or measurements are involved
perties are known as Fields
ic field - defines the size and shape of the molecule
trostatic field - defines electron rich/poor regions of molecule
rophobic properties are relatively unimportant
Advantages over QSAR

reliance on experimental values


n be applied to molecules with unusual substituents
t restricted to molecules of the same structural class
edictive capability

3D-QSAR
Method

mparative molecular field analysis (CoMFA) - Tripos


ld each molecule using modelling software
ntify the active conformation for each molecule
ntify the pharmacophore

OH
HO

HO

NHCH3

Build 3D
model
Active conformation Define pharmacophore

3D-QSAR
Method

mparative molecular field analysis (CoMFA) - Tripos


ld each molecule using modelling software
ntify the active conformation for each molecule
ntify the pharmacophore

OH
HO

HO

NHCH3

Build 3D
model
Active conformation Define pharmacophore

3D-QSAR
Method
Place the pharmacophore into a lattice of grid points

.
.

.
.
Grid points

Each grid point defines a point in space

3D-QSAR
Method
Position molecule to match the pharmacophore

.
.

.
.
Grid points

Each grid point defines a point in space

3D-QSAR
Method
A probe atom is placed at each grid point in turn

.
.

Probe atom

.
.

Probe atom = a proton or sp3 hybridised carbocation

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

3D-QSAR
Method

The closer the probe atom to the molecule, the higher the
steric energy
Define the shape of the molecule by identifying grid points
of equal steric energy (contour line)
Favorable electrostatic interactions with the positively
charged probe indicate molecular regions which are
negative in nature
Unfavorable electrostatic interactions with the positively
charged probe indicate molecular regions which are
positive in nature
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
Identify steric and electrostatic fields which are favorable
or unfavorable for activity

3D-QSAR
Method
.
. . .

Tabulate fields for each


compound at each grid point

Compound
Biological
Steric fields (S)
Electrostatic fields (E)
activityat grid points (001-998)
at grid points (001-098)
S001S002S003S004S005 etcE001E002 E003 E004E005 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

3D-QSAR
Method
Define fields using contour maps round a representative molecule

3D-QSAR CASE STUDY


Tacrine
Anticholinesterase used in the treatment of Alzheimers disease

NH2

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
NH2
R1

R2

Substituents: CH3, Cl, NO2, OCH3, NH2, F


(Spread of values with no correlation)
1
1 2
1
- .09 MR(R
) +1.43F(R,R ) +7.00
Log C pIC50= 3

Conclusions
Large groups at position 7 are detrimental
Groups at positions 6 & 7 should be electron-withdrawing
No hydrophobic effect

3D-QSAR CASE STUDY


CoMFA Study
Analysis includes tetracyclic anticholinesterase inhibitors (II)
NH2
R1

R2

R3

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

3D-QSAR CASE STUDY


Possible Alignment
Good overlay but assumes similar binding modes

Overlay

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)
while still bound to the binding site (in silico)
The complex was minimized to find the most stable binding mode
for structure II
The binding mode for (II) proved to be different from tacrine

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

Blue areas - addition of steric bulk increases activity


Red areas - addition of steric bulk decreases activity

3D-QSAR CASE STUDY


Prediction
6-Bromo analogue of tacrine predicted to be active (pIC50 = 7.40)
Actual pIC50 = 7.18

NH2

Br