Pharmacophore target

Targeted libraries have been most effective when based upon the display of diverse functionality about a minimal mechanism-based pharmacophore targeting an enzyme family. Early successes with this approach were first achieved with proteases.1221 Our own efforts to design libraries which target enzyme families require that the minimal pharmacophore serves as the site for attachment to solid support.1231 The pharmacophore is the only invariant part of the inhibitor structure, which... 

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. 

Nonbenzodiazepine Benzodiazepine Receptor Ligands. The simultaneous discovery of the molecular target for the BZs, the GABA /BZ receptor complex, by two teams of workers (34,35) resulted ia the identification of a number of atypical or anxioselective anxiolytics that, whereas not having the BZ pharmacophore, interacted direcdy with the central BZ receptor. The anxioselective nature of such agents was considered to be... 

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). 

Pharmacophore. A part within a dmg molecule which is believed to play a major role in interaction of that dmg with its target. There may be more than one pharmacophoric site within the chemical stmcture of a dmg molecule. 

A group of compounds is selected which possess a common three-dimensional pharmacophore, i.e. a configuration of chemical groups that presumably interact with the target receptor or enzyme. The compounds are then aligned in space by translation and rotation, for example on the basis of their similarity with a known... 

Medicinal chemists have a distinct advantage in pursuing mechanism-of-action studies because it is possible to synthesize a series of structurally related congeners and measure their biological activity. A correlation between activity and particular structural features not only helps to identify the pharmacophore, or active moiety imbedded within the molecule, but also may establish critical requirements or complementarity for the biological target or receptor for the particular drug class. 

In many respects the fragment approach is ideally suited to projects which have X-ray crystal structures available. The fragments are small and relatively weak binders, but they often only possess one pharmacophoric element that binds to a specific feature on the target. If this interaction is identified by X-ray structure determination, then project teams can propose specific plans which maintain that critical interaction, and ideally optimize binding through other vectors in their fragments. 

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