Receptor excluded 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. 

The SMER, Fig. (27), is similar model to estrogen receptor excluded volume (RExV) postulated by Kym et al. [212]. The volume of die SMER was 424.7 A3. Most flavonoid skeletons (A-C rings) lay into die SMER, however, the prenyl (geranyl) groups existed out of die SMER as shown in Fig. (27). 

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...

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.

Greenidge, P.A., Carlsson, B., Biadh, L.G., and Gillner, M. Pharmacophores incorporating numerous excluded volumes defined by x-ray crystallographic structure in three-dimensional database searching application to the thyroid hormone receptor./. Med. Chem. 1998, 41, 2503-2512. 

In a paper published in 2000 by Norinder [30], Catalyst was used for the first time to build a common feature pharmacophore hypothesis for HIV-1 protease inhibitors, which was then refined using in-house software (HypoOpt), after having added to it some hundreds of excluded volume spheres. These were actually derived from the X-ray structure of an inhibitor complexed to the enzyme. The aim of the approach was to obtain a computational model with some improved predictive power with respect to the corresponding hypothesis derived without receptor information. 

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. 

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