Pharmacophoric conformations

Similar conformational analyses were performed for inactive compounds, and inactive compounds in pharmacophoric conformations were superimposed with the active compounds to determine steric limitations in the active site. Where appropriate, the geometry of each inactive molecule was obtained by modifying the chemical strucmre of the relevant active analogs followed by the energy minimization of the resulting structure. 

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. 

G. Melacini, Q. Zhu, G. Osapay, M. Goodman, A Refined Model for the Somatostatin Pharmacophore Conformational Analysis of Lanthionine-Sandostatin Analogs , J. Med. Chem. 1997, 40, 2252-2258. 

The four possible stereoisomers of the diastereomeric mixture of ( )-2-(lH-imidazol-4-yl)-cyclopropylamine (17) have not been separated yet (except very recently both tram isomers (Table 4) [25]), but as a result of this molecular modelling study it was observed that a congruent pharmacophoric conformation can only be adopted by the two tram configured isomers [24]. The conformationally restricted pyrrolidine derivatives immepyr (21) and SCH 50971 (22) support this pharmacophore... 

Calculation Pharmacophores Conformers Shape Score 1 Shape 2 Shape 3... 

However, it is unclear whether the hairpin conformation is also the conformation at the CBi receptor active site. Recent biophysical work on the conformational properties of anandamide in the membrane provide evidence for a more extended conformation for the C20 chain (A. Makriyannis and X. Tian, unpublished results) and suggest alternative CBi pharmacophoric conformations. 

Fig. 24.1 Schematic drawing representing the FITIT procedure. The conformational space is reduced by pairwise superpositioning of energetically allowed conformations of the different chemical classes. A second superpositioning step for all selected FITIT pairs finally yields the common pharmacophoric conformations.

In order to obtain comparable energy data, the interaction geometries of the complexes are generated for all the ligands in an absolutely corresponding manner. All ligands are kept in the pharmacophoric conformation and location. Hydrophobic and polar amino acids mimicking equivalent... 

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. 

D substructure search is usually known as pharmacophore searching in QSAR. In all of the 3D search methods the conformational flexibility creates considerable difficulties. 

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... 

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. 

D database searching. As each conformation is generated an appropriate bit is set in the binary key. At me, the binary key appropriate to the pharmacophore is set up and compared with the keys in the database. 

Pharmacophore keys Family of low-energy conformations See Section 12.9.4... 

Fig. 12.27 The generation of 3-centre pharmacophore keys, illustrated using benperidol. Two different conformations are shown, together with two different combinations of three pharmacophore points.

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