Sphere, excluded volume

LigandScout pharmacophores solely consist of chemical features classified as layers 3 and 4 (Table 6.2). Visualization mainly distinguishes between point and vector features point features (layer 4) are defined as a center with a tolerance this group encompasses hydrophobic, positively ionizable and negatively ioniz-able areas, in addition to excluded volume spheres. Hydrogen donors, acceptors and donor-acceptor pairs belong to the vector features group. 

Point features are rendered as spheres with different colors to differentiate them (Fig. 6.5) hydrophobic/lipophilic features are drawn in yellow and positive and negative ionizable features are drawn in red and blue, respectively. Excluded volume spheres use a dark gray color to signify their meaning. 

Fig. 6.6 Pharmacophore of complex lopj, consisting of four lipophilic aromatic points (light gray spheres), three vectorized HBA (arrows) and excluded volume spheres (dark gray spheres).

The resulting pharmacophore model contains four lipophilic aromatic areas, two acceptors and eight excluded volume spheres. The same screening experi-... 

As already stated in the Introduction, a problem that sometimes arises in pharmacophore approaches is the need to take into account possible adverse steric interactions between inactive compounds in a dataset and the target protein counterpart In these situations, the definition of ligand-forbidden zones by means of the addition of excluded volume spheres to a pharmacophore is nowadays considered a reasonable and effective improvement. 

Excluded Volume Spheres in Structure-based and Ligand-based Pharmacophore Studies... 

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. 

The possibility of adding automatically excluded volume spheres to ligand-based pharmacophores, thus accounting for steric hindrance problems, has re-... 

Here, the coordination interaction plus three aromatic rings (RA1, RA2 and RA3) and two excluded volume spheres (EV1 and EV2) were found by Catalyst... 

The coordination interaction, one aromatic ring, two hydrophobic features and two excluded volume spheres make up the final model (shown in Figure... 

Fig. 12.8 Compound 15g (in yellow) mapped on to MOD3 (the final pharmacophore). Pharmacophore features are color coded blue for the unsubstituted aromatic nitrogen (UNA), red for aromatic ring (RA), green for hydrophobic (HY1 and HY2). In black are shown the excluded volume spheres (EV1 and EV2).

In structure-based pharmacophore modeling, excluded volume spheres can be placed at atoms forming the binding site, a feature that has also been included in LigandScout. For faster screening and less restrictive models, LigandScout alternatively allows for the placement of only a few excluded volume spheres at the lipophilic side-chain residues that are in contact with hydrophobic features in the ligand. We have found that excluded volume... 

An explicit specification of inactive compounds as well as the maximum number of excluded volume spheres, and softening of excluded volume spheres during fitting can be adjusted by the user. 

The pearl necklace model (Fig. 1.3[b]) is a somewhat more useful model, although it is strictly athermal but, by a proper choice of the ration h/ between the radius h of the excluded volume sphere around each bead and the bond length I, one can ensure automatically that chains cannot cross each other if they respect excluded volume restrictions (no spheres are allowed to overlap apart, possibly, from subsequent ones if one chooses l l[Pg.12]

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