Pharmacophore chiral

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). 

Biocatalysis has emerged as an important tool for the enantioselective synthesis of chiral pharmaceutical intermediates and several review articles have been published in recent years [133-137]. For example, quinuclidinol is a common pharmacophore of neuromodulators acting on muscarinic receptors (Figure 6.50). (JJ)-Quinudidin-3-ol was prepared via Aspergillus melleus protease-mediated enantioselective hydrolysis of the racemic butyrate [54,138]. Calcium hydroxide served as a scavenger of butyric acid to prevent enzyme inhibition and the unwanted (R) enantiomer was racemized over Raney Co under hydrogen for recycling. 

As part of the processing within this system, molecules can be cleaned (chirality, ionization). Conformers can also be generated on-the-fly when performing the database search. In addition to conformations, indexing of a database can be done by adding pharmacophore sites. Partial match of the hits on a pharmacophore query is allowed. The pharmacophore search hits are ranked using a fitness function. 

Henkel et al. did not differentiate the natural products from natural product derivatives. The descriptors they used for comparison were molecular weight, number and type of hetero atoms, pharmacophore groups (e.g. CO, CONH, OH, CN, NH, etc), bridgehead atoms, rotatable C C bonds, rings per molecule, chiral centres per molecule and rotatable bonds per molecule. 

Generation of every three-centre pharmacophore is the method most commonly used however, since three-centre pharmacophores do not represent three-dimensional information such as volume or chirality, four-centre pharmacophores are becoming increasingly common. 

Using 4-point pharmacophores enables chirality to be handled and adds some elements of volume/shape linked to electronic properties, increasing separation in similarity and diversity studies. There is a large increase in the number of potential pharmacophores that need to be considered. For example, using six possible feature types for each point, and 10 distance ranges (bins) for each feature-feature distance, the number of potential pharmacophores increases from 33 000 for 3-point pharmacophores to 9.7 million for 4-point pharmacophores [14—16]. Reducing the number of distance bins to seven reduces these numbers to 9000 and 2.3 million respectively. 

The extension to four-point pharmacophores enables chirality to be handled and enables some elements of volume/shape linked to... 

Some research groups have extended the atom-pair descriptors to three-point (triplets) and four-point (quartets) pharmacophore descriptors (35,37,76,81) as described in section 2. These descriptors have a potentially superior descriptive power, and a perceived advantage over atom pairs is the increased "shape" information (intrapharmacophore distance relationships) content of the individual descriptors (37a). The quartet (tetrahedral) four-point descriptors offer further potential 3D content by including information on volume and chirality (37a, 82), compared with the triplets that are components of the quartets and represent planes or "slices" through the 3D shapes. 

We have analyzed (14J the molecular structures of these semirigid chiral ligands and, in both, we have identified a common chiral pharmacophore, namely a phenyl ring and a nitrogen atom, uniquely juxtapositioned one to the other, which is contained in an extended phenethylamine moiety. We have since shown that the same pharmacophore is present in the DAR antagonist (+)-octo-clothepin,III,as well as in several other DAR ligands (19). 

Applying supervised machine learning techniques, Li et al. [66] proposed a model that differentiates substrates from nonsubstrates of P-gp based on a simple tree using nine distinct pharmacophores. Four-point 3D pharmacophores were employed to increase the amount of shape information and resolution and possessed the ability to distinguish chirality. Relevant features were hydrogen-bond acceptors, hydrophobic-ity indices, and a cationic charge. 

Topographic pharmacophoric patterns may conveniently be defined in terms of atom types and interatomic distance.7 Distance geometry has been shown to uniquely define 3-dlmenslonal molecular structures, except for their chirality.8 Properties of pharmacophoric patterns which have been defined Include chirality (stereochemistry). 

This is because stereochemistry nomenclature is merely a formal description of the real molecular structure. The correct spatial shape of the pharmacophore is not represented at all. A correct description of stereochemistry is possible with descriptors based on the three-dimensional structure only. Molecules can show the same pharmacophore (i. e., same three-dimensional arrangement of pharmacophore centers) but different chirality according to chirality nomenclature. 

The 4-point pharmacophore keys can encode information either on the presence/absence of the possible pharmacophores or on their occurrence frequency. In the latter case, the occurrence frequency of each pharmacophore is normalized by the conformational ensemble count [Good, Gho et al., 2004[. Moreover, to account for chirality, for all chiral 4-point pharmacophores, separate bins are set in the bit strings for the two enantiomers. Finally, the similarity/diversity measure between the two 4-PPP keys is based on the Tversky association coefficient. 

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