Direct approaches, pharmacophore

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

Another approach consists of identifying chemical pharmacophore features that interact directly with the bound ligand. They can be summarized as hydrophobic centers, H-bond donors and acceptors, positive and negative charges, aromatic centers, etc. These surface... 

Ji, H.T., Stanton, B.Z., Igarashi, J., Li, H.Y., Martasek, P., Roman, L.J., Poulos, T.L., Silverman, R.B. Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors. J. Am. Chem. Soc. 2008, 130, 3900-14. 

Pharmacophore profiles are defined that represent the set of all the pharmacophores found across the conformers of a series of conformers or series of molecules. Each pharmacophore added to the profile has to be unique. This profile will help in showing the spread of pharmacophores across the conformational space of a molecule or a series of molecules. No sum of the exhibited pharmacophores or normalization is done. There is no direct graphical representation of pharmacophore models. The pharmacophores can be saved to a file in CSV format that can be imported into a MySQL or Oracle database. This approach permits the use of standard SQL queries to extract common pharma-... 

One of the difficulties with this type of approach is that the quality of the results depends directly on the quality of the initial pharmacophore model, which can sometimes prove challenging. A particular hazard is that active compounds can have different binding modes, even in a closely related series of inhibitors. This algorithm partially addresses that problem, since it does not take as a fundamental assumption that all molecules bind in the same orientation, however further tools to identify alternative binding modes would be helpful. Overall it shows potential to be a powerful tool to direct library design. 

Furthermore, a pharmacophore can be directly used as the search query for 3D database mining, which is a common and efficient approach for discovery of lead compounds... 

A hybrid of the one-bead-one-peptide and positional-scanning library formats (see Section 4.3.V.3.2.2) is presented by an approach termed library of libraries ,which is directed toward the identification of pharmacophore motifs, i.e. structural motifs necessary for the bioactivity of interest, rather than the complete structures of individual active compounds. This library format enables the identification of specific, i.e. nonreplaceable, positions of a peptide with a bioactivity of interest versus unspecific positions, which can be replaced by a variety of different amino acids without loss in activity. In the example presented,a hexapeptide library is generated as 160000 (20 x20) sublibraries (beads), which represent all possible combinations of three defined and three mixture positions within the hexapeptide framework, i.e. 8000 (20 ) different combinations of three amino acids at the defined positions within a given arrangement of the hexapeptide multiphed by 20 possible different arrangements of three defined and three mixture positions. While the defined positions are coupled using the DCR method,01 the mixture positions are introduced by the coupling of amino acid mixtures. 

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