Biomedical Engineering Reference
In-Depth Information
A
B
C
A set of active
compounds
A
B
C
Conformational
analysis
Δ
G
conf
Δ
G
conf
A
A
A
A
Alignment
B
B
B
C
C
C
C
Proposed bioactive
conformations
Identify repulsive
steric interaction
FIGURE 3.1
Basic principles of the development of a 3D-pharmacophore model.
is a collection of pharmacophore elements and the concept of “3D-pharmacophore” may be used
when the relative spatial positions of the pharmacophore elements are included in the analysis.
Thus, a 3D-pharmacophore consists of a specii c 3D-arrangement of pharmacophore elements.
The basic principles of the development of a 3D-pharmacophore model are illustrated in
Figure 3.1. On the basis of conformational analysis of a set of active molecules with pharmacophore
elements A, B, and C, a low energy conformation of each molecule is selected for which the pharma-
cophore elements of the molecules overlap in space as shown in the i gure. Conformational energies
in ligand-protein binding are discussed in more detail in Chapter 1. The selected conformations are
the putative bioactive conformations of the molecules and the overlapping pharmacophore elements
and their spatial positions make up the 3D-pharmacophore.
The development of a 3D-pharmacophore model requires that a number of active compounds
and their afi nities for the receptor in question are available. The necessary number of compounds
depends mainly on the conformational l exibility of the ligands. In the case of highly l exible mole-
cules, the development of a pharmacophore model generally requires a larger number of compounds
compared to the case in which the compounds are less l exible.
In addition to active compounds, it is highly useful that a number of inactive compounds also
are available. These may, as will be demonstrated in the following text, fruitfully be used to iden-
tify regions of sterically repulsive ligand-receptor interactions and thus provide an estimate of the
dimensions of the binding cavity.
3.4 A 3D-PHARMACOPHORE MODEL FOR FLAVONES
BINDING TO THE BZD SITE
The development of the pharmacophore model will be i rst discussed in terms of the different steps
in Figure 3.1. The molecular structure and atom numbering of l avone (
3.1
) is shown in Figure 3.2.
The carbonyl group, the ether oxygen, and the two phenyl rings are common to all active com-
pounds in the l avone series and are necessary for the activity at the BZD site. These are the basic
pharmacophore elements. The identii cation of the bioactive conformation in the l avone series
is straightforward. Flavone (
3.1
) has a very limited conformational l exibility. The only torsional
degree of freedom is the rotation about the 2-1
bond connecting the phenyl ring to the bicyclic
system. Conformational analyses of the available compounds in the l avone series and compari-
sons with the corresponding experimental afi nities show that only compounds in which the entire
l avone skeleton is planar or close to planar in the global energy minimum are compatible with a
′
