Biomedical Engineering Reference
In-Depth Information
O
O
O
H
3
C
H
3
C
6
5´
O
O
O
4´
CH
3
3´
1.3
K
i
= 4200 nM
1.4
K
i
= 180 nM
1.5
K
i
= 4400 nM
O
O
H
3
C
H
3
C
CH
3
O
O
CH
3
1.6
K
i
= 29 nM
CH
3
1.7
K
i
> 1500 nM
FIGURE 1.13
Afi nities of methyl-substituted l avones binding to the benzodiazepine site of GABA
A
receptors.
When a methyl group is introduced in the 6-position (
1.4
), the afi nity is increased by a factor of
23. This indicates that the methyl group can be very well accommodated in a lipophilic cavity in
the binding site and that the afi nity increase is due to hydrophobic interactions including disper-
sion interactions. An introduction of a methyl group to the 4
-position in
1.4
to give
1.5
results in a
24-fold decrease of the afi nity. This is most likely due to repulsive vdW interactions between the
4
′
-methyl group and the receptor giving an indication of the dimensions of the binding site in this
region. An introduction of a 3
′
-methyl group in
1.4
to give
1.6
increases the afi nity by a factor of
6. This is a signii cantly lower afi nity increase than shown by the 6-methyl group in
1.4
. Thus, the
two receptor regions in the vicinities of the 6- and 3
′
′
-positions clearly have different properties.
The region in the vicinity of the 3
-position can accommodate a methyl group but the i t between
the methyl group and the receptor is not as good as in the case of the 6-methyl compound
1.4
.
This is supported by the modest change in afi nity when larger substituents are introduced in the
3
′
-methyl group in
1.6
giving
1.7
strongly
decreases the afi nity by a factor of more than 52. This is undoubtedly due to strong repulsive vdW
interactions with the receptor. This identii es another steric repulsive receptor region adjacent to
that identii ed by compound
1.5
. This example shows that conclusions drawn on the basis of a few
compounds may provide valuable information on the properties of the protein binding site. Such
information may be fruitfully used in the design of new compounds.
′
-position (see Chapter 3). Finally, the introduction of a 5
′
FURTHER READINGS
Ajay, A. and Murcko, M. A. 1995. Computational methods to predict binding free energies in ligand-receptor
complexes.
J. Med. Chem
. 38:4953-4967.
Andrews, P. R. 1993. Drug-receptor interactions. In
3D QSAR in Drug Design: Theory, Methods and
Applications
, Kubinyi, H. (ed.), ESCOM Science Publishers B.V., Leiden, the Netherlands, pp. 583-618.
Andrews, P. R., Craig, D. J., and Martin, J. L. 1984. Functional group contributions to drug-receptor interactions
J. Med. Chem
. 27:1648-1657.
Boström, J., Norrby, P.-O., and Liljefors, T. 1998. Conformational energy penalties of protein-bound ligands.
J. Comput. Aided Mol. Des
. 12:383-396.
