Professional Documents
Culture Documents
Notes
OH
HO NHCH3
HO
Build 3D
model
Active conformation Define pharmacophore
3D-QSAR
Method
OH
HO NHCH3
HO
Build 3D
model
Active conformation Define pharmacophore
3D-QSAR
Method
.
.
. .
.
Grid points
.
.
. .
.
Grid points
.
. Probe atom
. .
.
.
. Probe atom
. .
.
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
.
. . .
.
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
NH2
N
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 9
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
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
Overlay
3D-QSAR CASE STUDY
X-Ray Crystallography
NH2
Br N