Library design target structure-based

The practical utility of the target-structure-based approach in the design of chemical libraries is still limited because of the requirement of quality crystallographic data, detailed knowledge of the ligand binding mode, and... 

TABLE 15.1 Specialized Computational Technologies for Target Structure-Based Design of Combinatorial Libraries... 

We call focused, or biased, or similarity based the libraries designed using structural information (a compound active on the target, or on a similar target) or a rational hypothesis and allowing the library structure to focus on very specific features. The main properties of such libraries are shown in Fig. 5.4. 

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). 

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... 

A.V., Tkachenko, S.E., Ivashchenko, A.A., and Savchuk, N.P. Structure-based versus property-based approaches in the design of G-protein-coupled receptor-targeted libraries. /. Chem. Inf. Comput. Sci. 2003, 43, 1553-1562. 

Figure 3. Approaches to cluster protein targets for screening of small molecule libraries. Currently, protein targets are clustered based on functional or amino acid sequence similarity (left). We propose to cluster proteins purely based on structural similarity of protein cores and to apply this clustering to compound library design (right).

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