Pharmacophor

The JME can also serve as a query input tool for structure databases by allowing creation of complex substructure queries (Figure 2-130), which are automatically translated into SMARTS [22]. With the help of simple HTML-format elements the creation of 3D structure queries is also possible, as were used in the 3D pharmacophore searches in the NCI database system [129]. Creation of reac-... 

The Web-based graphical user interface permits a choice from numerous criteria and the performance of rapid searches. This service, based on the chemistry information toolkit CACTVS, provides complex Boolean searches. Flexible substructure searches have also been implemented. Users can conduct 3D pharmacophore queries in up to 25 conformations pre-calculated for each compound. Numerous output formats as well as 2D and 3D visuaHzation options are supplied. It is possible to export search results in various forms and with choices for data contents in the exported files, for structure sets ranging in size from a single compound to the entire database. Additional information and down-loadable files (in various formats) can be obtained from this service. 

The search for structural fragments (substructures) is very important in medicinal chemistry, QSAR, spectroscopy, and many other fields in the process of perception of pharmacophore, chromophore, or other -phores. 

D substructure search is usually known as pharmacophore searching in QSAR. Generally speaking, there are two major approaches to it topological and chemical function queries. These two techniques are based on a slighfly different philosophy and usually provide different results [31]. 

Application of the CCM to small sets (n < 6) of enzyme inhibitors revealed correlations between the inhibitory activity and the chirality measure of the inhibitors, calculated by Eq. (26) for the entire structure or for the substructure that interacts with the enzyme (pharmacophore) [41], This was done for arylammonium inhibitors of trypsin, Di-dopamine receptor inhibitors, and organophosphate inhibitors of trypsin, acetylcholine esterase, and butyrylcholine esterase. Because the CCM values are equal for opposite enantiomers, the method had to be applied separately to the two families of enantiomers (R- and S-enantiomers). 

The 3D pharmacophore search with C(5)ROL in the Biochemical Pathways database provided 13 different molecules as hits. To further limit the number of hits, the additional restriction was imposed that the hits should have only two hydrogen... 

Figure 10.3-25. a) Structure of diethylstilbestrol (DES) b) 3 D pharmacophore query of DES two hits were found c) estrone and d) estradiol. 

Flexible 3D alignment of a set of ligands binding to the same target and/or CoMFA analysis allowing the perception of a pharmacophore for this target. 

Metabolism is still a barrier to be overcome. Some QSAR, pharmacophore, protein, and rule-based models are available to predict substrates and inhibitors of a specific cytochrome P450 isoenzyme [47-55]. 

In a recent review the pharmacophore identification programs Catalyst, DISCO, and GASP have been compared [83]. 

There are two problems to consider when calculating 3D pharmacophores. First, unless the molecules are all completely rigid, one must take account of their conformational properties The second problem is to determine which combinations of pharmacophoric groups are common to the molecules and can be positioned in a similar orientation in space. More than one pharmacophore may be possible indeed, some algorithms can generate hundreds of possible pharmacophores, which must then be evaluated to determine which best fits the data. It is important to realise that all of these approaches to finding 3D pharmacophores assume that all of the molecules bind in a common manner to the macromolecule. 

A variant of distance geometry called ensemble distance geometry [Sheridan et al. 1986] can be used to simultaneously derive a set of conformations with a previously defined set of pharmacophoric groups overlaid. Ensemble distance geometry uses the same steps as... 

Fig. 12.10 Two ACE pharmacophores identified by the constrained systematic search [Dammkoehler et al. 1989],...

Fig. 12.12 Four molecules used to derive the nicotinic pharmacophore by distance geometry and the pharmacophore obtained.

In a related way, ensemble molecular dynamics derives a pharmacophore using restrained molecular dynamics for a collection of molecules. A force field model is set up so that none of the atoms in each molecule sees the atoms in ainy other molecule. This enables the molecules to be overlaid in space. A restraint term is included in the potential, which forces the appropriate atoms or functional groups to be overlaid in space. 

When many pharmacophoric groups are present in the molecule it may be very difficult to identify all possible combinations of the functional groups (there may be thousands of... 

One limitation of clique detection is that it needs to be run repeatedly with differei reference conformations and the run-time scales with the number of conformations pt molecule. The maximum likelihood method [Bamum et al. 1996] eliminates the need for reference conformation, effectively enabling every conformation of every molecule to a< as the reference. Despite this, the algorithm scales linearly with the number of conformatior per molecule, so enabling a larger number of conformations (up to a few hundred) to b handled. In addition, the method scores each of the possible pharmacophores based upo the extent to which it fits the set of input molecules and an estimate of its rarity. It is nc required that every molecule has to be able to match every feature for the pharmacophor to be considered. 

This rarity value is equated with the fraction of hits that would be returned by searching large database of diverse molecules with the full pharmacophore (all K features) or thi subset (with K—1 features) as appropriate. Labelling this fraction of hits as p(x) we nov define q x) as the fraction of the M active molecules (i.e. the molecules originally suppliet as input to the procedure) which match each of the K + possible classes. The overal configuration is scored using ... 

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