Pharmacophore-based ligand libraries

Fig. 4.1 Virtual screening tools can be categorized by the compound data to be screened (compound collection, combinatorial library, chemistry space) and the query type (structure-based, ligand-based, descriptor-based, pharmacophore-based). The output is always a list of compounds together with a score quantifying the fit to the query.

In another recent effort, Poulain and co-workers illustrate the improvements in efficiency that focused libraries can bring to early lead optimization. The authors describe the hit-to-lead optimization of J, opiate ligands, starting with a micromolar hit from HTS. Using a pharmacophore-based approach, several focused libraries were designed and synthesized, as illustrated in Scheme 8. Combining the results of these libraries suggested a series of chimeric compounds, which exhibited subnanomolar activity and improved physico-chemical properties. 

Pharmacophore-Based Ligand Libraries. The majority of pharmaceutical companies have relatively large chemieal libraries... 

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). 

In both the second and third approaches, the use of activity scores based on the positions in chemistry space of the virtual library products relative to the positions of known ligands of each individual target incorporates all of the information about known ligands, rather than just the common pharmacophoric features. The structural elements that convey specificity are not excluded in the design, as they may be in the first approach. 

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