Receptor essential volume

The essential feature of the AAA is a comparison of active and inactive molecules. A commonly accepted hypothesis to explain the lack of activity of inactive molecules that possess the pharmacophoric conformation is that their molecular volume, when presenting the pharmacophore, exceeds the receptor excluded volume. This additional volume apparently is filled by the receptor and is unavailable for ligand binding this volume is termed the receptor essential volume [3]. Following this approach, the density maps for each of the inactive compounds (in their pharm conformations superimposed with that of active compounds) were constructed the difference between the combined inactive compound density maps and the receptor excluded volume represents the receptor essential volume. These receptor-mapping techniques supplied detailed topographical data that allowed a steric model of the D[ receptor site to be proposed. 

Figure 4 Excluded volume for the Di agonist pharmacophore. The mesh volume shown by the black lines is a cross section of the excluded volume representing the receptor binding pocket. Dihydrexidine (see text) is shown in the receptor pocket. The gray mesh represents the receptor essential volume of inactive analogs. The hydroxyl binding, amine binding, and accessory regions are labeled, as is the steric occlusion region.

Excluded volume Excluded volume is the union of volumes of a set of active ligands that is available to the ligands interacting with the receptor. Subtraction of the volume in common with the volume of the active and inactive ligands from the volume of the inactive ligand leads to the receptor essential volume, i.e., the volume required by the receptor. 

One possible reason for the activity of R-ABA at a slow site, but not at the fast type, is that there is interference with receptor essential volume for the fast type, but not for the slow. This is shown in Milborrow s model [18] (Fig. 5), which has the side-chain equatorially oriented. With the side-chain anchored, inversion of configuration causes the 7 -methyl and the 6 -methyls to be on opposite sides, as shown. The axial methyl of R-ABA interferes in the fast site but not the slow, which is postulated as being more accommodating. Because it is now known that PA has significant physiological activity... 

Fig. 4. Molecular modeling of (-)-2l -THC ligands with different substitution in the C-1 side chain position using molecular mechanics/molecular dynamics. CB1/CB2 receptor-excluded volume map (redcontours and essential volume map (white grid for the C-1 subsite in zl -THC series. The red area represents the free space within the receptor region that accommodates high-affinity C-1 -substituted ligands, whereas, C-1 substituents falling within the white grid experience unfavorable or less favorable interactions at the binding site...

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