A 3dpharmacophore Model For Flavones Binding To The Bzd Site

The development of the pharmacophore model will be first discussed in terms of the different steps in Figure 3.1. The molecular structure and atom numbering of flavone (3.1) is shown in Figure 3.2. The carbonyl group, the ether oxygen, and the two phenyl rings are common to all active compounds in the flavone series and are necessary for the activity at the BZD site. These are the basic pharmacophore elements. The identification of the bioactive conformation in the flavone series is straightforward. Flavone (3.1) has a very limited conformational flexibility. 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 flavone series and comparisons with the corresponding experimental affinities show that only compounds in which the entire flavone skeleton is planar or close to planar in the global energy minimum are compatible with a

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6'

8 1

1'

2'

Flavone

Template molecule

Template molecule

Hydrophobic pharmacophore element

Hydrogen-bond acceptor

Hydrophobic pharmacophore element

Hydrogen-bond acceptor

Hydrogen-bond acceptor

Hydrophobic pharmacophore element

FIGURE 3.2 The structure and atom numbering of flavone (3.1), the flavone derivatives (3.2-3.4), the template structure (3.5) and the template structure mapped with four pharmacophore elements (two hydrogen-bond acceptors [green] and two hydrophobic pharmacophore elements [cyan]).

Hydrogen-bond acceptor

Hydrophobic pharmacophore element

FIGURE 3.2 The structure and atom numbering of flavone (3.1), the flavone derivatives (3.2-3.4), the template structure (3.5) and the template structure mapped with four pharmacophore elements (two hydrogen-bond acceptors [green] and two hydrophobic pharmacophore elements [cyan]).

significant affinity. The alignment of pharmacophore elements in Figure 3.1 is in this case trivial as all compounds in the series have the same molecular skeleton.

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