Diversity in Site-focused Libraries

Roe D.C. Molecular diversity in site-focused libraries. In Molecular Diversity in Drug Design, Ed. Dean P.M. and Lewis R.A., Kluwer, 1999. Ch. 7. 

Different strategies for combiningdiversity and structure-based design in site-focused libraries and the DOCK-based CombiBUILD algorithm are discussed in a review (125), as an example of how lead compounds can be rapidly identified by combining diversity with structure-based design in site-focused libraries. 

This chapter has reviewed the basic principles of computer-aided drug design, and several strategies of how it can be successfully integrated with combinatorial chemistry to develop highly effective site-focused libraries. Diversity plays a key role, as the more diverse set of compounds tested that fit the site-focused criteria, the more information is retrieved to improve the site-focused definition, which further directs the search in diversity space. In addition, if good hits are found, the information can be fed back to find compounds close in diverse space to the hit. This new paradigm for structure-based combinatorial chemistry should provide a powerful tool for rapid discovery of novel, potent lead compounds in the years to come. 

When used for relative similarity and diversity, only potential pharmacophores that contain the defined special centre-type are used. The frame of reference for similarity/diversity studies is thus changed to one that is focused on the feature of interest distances are now measured relative to this special centre. For example, the special centre could be the centroid of a substructure [10] such as biphenyl tetrazole or diphenylmethane, enabling the calculation and comparison of all 3D pharmacophoric shapes that contain this substructure the substructure is said to be privileged . For structure-based design, the potential pharmacophores in a site can be restricted to those that contain a specific site point (e.g. in a pocket, or at the entrance to a pocket). In the context of combinatorial library design, the relative measure can be those pharmacophoric shapes that contain a special site-point that represents where the attachment point for a reagent would be. In figure 1, the special point would be centre-type number 3, which can be reserved for this purpose. 

---