Biomedical Engineering Reference
In-Depth Information
pharmacophore, the compound shows only weak afi nity (
K
i
= 6400 nM). According to calculations,
an intramolecular hydrogen bond between the hydroxyl group and the carbonyl group is present in
the global energy minimum of the compound (Figure 3.9). In order to donate a hydrogen bond from
the hydroxyl group as required by the pharmacophore model, the intramolecular hydrogen bond has
to be broken giving a high conformational energy penalty (calculated to be 48 kJ/mol) and as a con-
sequence of this the afi nity is strongly decreased. Such conformational energy penalties may not be
taken properly into account by database searching programs. It is also highly advisable to examine
hydrogen bond distances to hydrogen bonding pharmacophore elements in the model to remove hits
with too long or too short hydrogen bonds.
3.6 PHARMACOPHORE-GUIDED OPTIMIZATION OF COMPOUND 3.14
Examining the i t of compound
3.14
to the pharmacophore model in Figure 3.8, three observations
of relevance for optimization of the compound with respect to afi nity can be made.
•
There is sufi cient space at the position of the CF
3
group to replace this group by a larger
substituent.
The ester ethyl group in
•
3.14
does not completely i ll out the cavity in comparison to
the bromo substituent in compound
3.2
(compa re the i t of the bromo substituent in tem-
plate molecule
3.12
in Figure 3.6). As this part of the shape is most probably a highly
hydrophobic/lipophilic pocket, it is essential for optimal afi nity to i ll it out as com-
pletely as possible. Replacement of the ester ethyl group by a propyl group is an obvious
possibility.
Compound
•
3.14
has two conformations with respect to rotation around the bond connect-
ing the ester group to the bicyclic ring system (Figure 3.10). A replacement of the ester
group by an amide group would stabilize the molecule in the bioactive conformation due
to the intermolecular hydrogen bond in the amide compound. This will give a smaller
conformational entropy loss for binding and a higher afi nity (for more details of entropy
effects in ligand binding see Chapter 1).
On the basis of these observations, a small series of compounds were synthesized and tested. The
most important compounds and their afi nities are shown in Figure 3.11.
NH
O
O
O
CF
3
Bioactive conformation
CF
3
O
NH
N
H
O
NH
CF
3
FIGURE 3.10
Conformational equilibria for compound
3.14
and its amide analogue.
