Receptor Essential Volumes and the Use of Exclusion Spheres

Inactive compounds, which fit the initial pharmacophore are, as mentioned earlier, useful to establish the dimensions of the receptor binding site, i.e., to determine parts of the binding cavity where substituents are in steric conflict with the receptor. Figure 3.3 shows four compounds (3.6-3.9)

FIGURE 3.3 Compounds 3.6-3.9 and the pharmacophore model including exclusion spheres (black).
FIGURE 3.4 Compound 3.10 and the pharmacophore with exclusion spheres (black) above and below the phenyl ring.

that all fit the initial pharmacophore model. The affinities of compounds 3.6-3.9 show that even small substituents in the 7-, 8-, 4'-, and 5'-positions of flavone give low affinities, which is most probably due to steric repulsive interactions with the receptor. The ligand-receptor repulsion sites (receptor essential volumes) are represented by black spheres (exclusion spheres) in Figure 3.3.

As mentioned in Section 3.4, only compounds in which the flavone skeleton is planar or close to planar in the global energy minimum are compatible with a significant affinity. This is exemplified by compound 3.10 in Figure 3.4. Due to strong steric repulsion between the bromo substituent and the 6'-hydrogen atom in the phenyl ring, this ring is calculated to be 63° twisted in the preferred conformation of 3.10. Furthermore, the energy required for the phenyl ring to be coplanar with the bicyclic ring system is as high as 26 kJ/mol. This high conformational energy makes 3.10 inactive at the BZD site. In order to distinguish between compounds that are planar or close to planar and those that are significantly nonplanar, exclusion spheres are positioned above and below the phenyl ring in the pharmacophore model as displayed in Figure 3.4.

3.4.3 Extension of the Pharmacophore Model

Other classes of compounds binding to the BZD site were examined for the possibility of adding more features to the pharmacophore model. Compound 3.11 (Figure 3.5) displays high affinity for the BZD site. The superimposition of 3.2 and 3.11 shown in Figure 3.5 indicates that both molecules may bind to the BZD site in the same manner. The presence of an NH group in 3.11, which may be hydrogen bonding to the receptor, makes it of interest to include this as an additional feature in the pharmacophore model. This may be accomplished by extending the template molecule 3.5 to include an NH group in the 6'-position as shown for the updated template molecule 3.12 in Figure 3.6. The updated pharmacophore model including the new pharmacophore element is also shown in Figure 3.6. The final pharmacophore model also includes a "shape" (in light gray), which is the van der Waals (vdW) volume of the template molecule 3.12. The "shape" gives an estimate of the available space for ligand binding in the receptor binding cavity.

Using the updated pharmacophore model, compound 3.13 was designed and synthesized as a test for the validity of the new pharmacophore feature. The affinity of this compound was found to be 0.9 nM, which makes it the highest affinity compounds in the flavone series with an affinity

FIGURE 3.6 Compound 3.11, the initial template molecule 3.5, the new template molecule 3.12, and the updated pharmacophore model with the new hydrogen-bond donor pharmacophore element (magenta) included.
Br

3.13

FIGURE 3.7 Compound 3.13 fitted to the pharmacophore model.

4500-fold higher than that of the parent flavone 3.1 as a result of the addition of only three properly placed substituents. Compound 3.13 is shown fitted to the final pharmacophore model in Figure 3.7.

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