In order to develop a computer representation of the pharmacophore model, which also includes information on the available space at important substituent positions (the last step in Figure 3.1), and to extend the simplistic pharmacophore model described earlier to include representations of interactions of pharmacophore elements with receptor sites, three substituted flavones (3.2-3.4) shown in Figure 3.2 were selected. Since small substituents in the 6-position increases the affinity, compound 3.2 with a bromo substituent in the 6-position was selected. Compound 3.3 with nitro groups in the 5- and 3'-positions was selected due to the favorable effect on the affinity for small substituents in these positions. Finally, compound 3.4 was selected as a representative of compounds in the available series that carry a large substituent in the 3'-position but still display a reasonable receptor affinity. Since all three compounds have the same skeleton, they were for simplicity merged into a single template molecule (3.5) displaying all the important features of 3.2-3.4. Alternatively, each of compounds 3.2-3.4 could have been analyzed by the computer program CATALYST for common pharmacophore elements.
The template molecule 3.5 was used as input to the widely used computer program CATALYST (Accelrys Software Inc.), which analyzes molecules in terms of pharmacophoric features and displays the pharmacophore elements as spheres. An advantage of this approach is that the pharmacophore model representation produced by CATALYST explicitly includes the physicochemical properties of the pharmacophore elements and that the model directly can be used for database searching as will be described in the following text. The physicochemical properties of the predefined pharmacophore elements in CATALYST are hydrogen-bond acceptor, hydrogen-bond donor, hydrophobic (aliphatic or aromatic), negative or positive charge, negatively or positively ionizable, and ring aromatic. In order to allow for variations in the geometry of the interaction between a ligand and its receptor, distance variation as well as angle variation is taken into account. For instance, a hydrogen-bond acceptor is defined by a distance from the atom, which accepts a hydrogen bond to the site that donates the hydrogen bond with an allowed geometrical variation at both ends. These allowed variations are defined by spheres and the optimal interaction is defined by the center of the spheres.
The resulting initial CATALYST pharmacophore model with the pharmacophore elements of the flavone skeleton is shown in Figure 3.2 (bottom right). The carbonyl oxygen atom and the ether atom are mapped as hydrogen-bond acceptors (green spheres), while the phenyl rings are mapped as hydrophobic pharmacophore elements (cyan spheres). It should be noted that these are both mapped as a single sphere whereas the pharmacophore elements involving the carbonyl group and the ether oxygen are displayed as two spheres in order to take the direction of the modeled hydrogen-bond interaction into account. For example, the sphere centered at the carbonyl oxygen in Figure 3.2 represents the ligand side (the hydrogen bond accepting side) of the hydrogen-bond interaction whereas the outer sphere represents the receptor side (the hydrogen bond donating site) of the hydrogen bond.
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