Tolerance spheres

It is noticeable that allowing tolerances to vary led HypoRefme to reduce tolerance spheres significantly. These more stringent location constraints reduce the number of alternate mappings, therefore allowing a model with good statistics... 

Represented as tolerance spheres. Aromatic rings not recognized as hydro-phobic areas Represented as position with tolerance and ring plane orientation... 

Represented as tolerance spheres, no explicit charges necessary Definition and customization through SMARTS patterns with associated geometry attributes... 

Geometric constraints depend on selected pharmacophore scheme. Features located at heavy atoms with tolerance sphere. 

Represented as tolerance spheres, require charges (cationic and anionic)... 

Acceptor and donor features positioned on heavy atom with tolerance sphere. (Layer 3 feature) Max. one donor or acceptor feature per atom... 

Aromatic features can be modeled as layer 4 point features or as layer 3 features. In Catalyst, Phase, and LigandScout these features are also attributed with a ring plane normal defining the spatial orientation (layer 3 feature). In MOE, the selected pharmacophore scheme determines whether a ring plane orientation constraint is included or if aromaticity is modeled as a pure point feature with a tolerance sphere. 

The next step is database search hit evaluation and selection. Compounds that have at least one conformation satisfying the geometric requirements and possess functional groups residing within the respective tolerance spheres of the pharmacophoric features are considered to be hits (i.e.. potential candidates for biological testing). A number of additional criteria are used in the selection of compounds for biological evaluation and experimental validations to achieve maximum efficiency in the discovery of lead compounds. 

Figure 13.2 A typical Catalyst pharmacophore, where different colors indicate different chemical features and the spheres define tolerance spaces that each chemical feature would be allowed to occupy. See color plate.

Influence of surface oxidation, 12-28 Potential energy surface, 66-73 Reaction order, 21 -22 Tafel slope, 18-20, 276-277, 297 Oxygen tolerance, 618-620 Outer sphere electron transfer, 33-38... 

An observation regarding HSAB theory here is that metal ions that are soft in aqueous solution must not only be able to form covalent M-L bonds, but also must have a loose enough coordination sphere to tolerate potentially adverse steric effects such as bulky donor atoms or substituents on a ligand. For a soft Zn(II) ion to be produced in zinc metalloenzymes, its coordination number must drop from six in the... 

The chemical feature definitions described in the following sections are all categorized into hydrogen bond interactions, which are described as layer 3 features, and also into charge interactions and lipophilic interactions, which are represented as level 4 features. All current layer 4 features are represented as points with a tolerance radius forming a sphere, whereas layer 3 features are represented by vectors. The chemical feature definitions are specified in Daylight SMARTS notation [37] (listed in detail in Table 6.2) and directly imported into... 

Similarly to the concept of the Catalyst software package [35, 40], hydrophobic areas are implemented in the form of spheres located in the center of hydro-phobic atom chains, branches or groups. First, a hydrophobicity scoring function pursuant to the Catalyst definition is implemented. As a next step, the algorithm checks if an ensemble of adjacent atoms is able to attain a sufficient overall hydrophobicity score. If this condition is met and a hydrophobic area in the macromolecule exists, a level 4 feature consisting of a sphere with a tolerance... 

A sphere with a tolerance radius of 1.5 A represents an ionizable feature and is added for the case that a reversely charged ionizable feature can be found on the macromolecule side within a plausible distance range. This interval is set to 1.5-5.6 A and is user-adjustable. 

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. 

Fig. 15.9 Mapping of three agonists on hypothesis 1 [(a) L-AP4, (b) (S)-4-PPG and (c) ACPT-I, all top views, and (d) ACPT-I, side view along the black arrow in (c)]. The green spheres represent the tolerances surrounding projected points of H-bond acceptor...

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