Methods for computer-aided chemical biology. Part 1: Design of a benchmark system for the evaluation of compound selectivity.

Computational drug design and discovery methods have traditionally put much emphasis on the identification of novel active compounds and the optimization of their potency. For chemical genetics and genomics applications, an important task is the identification of small molecules that are selective against target families, subfamilies, or individual targets and can be used as molecular probes for specific functions. In order to develop or tune computational methods for such applications, there is a need for molecular benchmark systems that focus on compound selectivity, rather than biological activity (in qualitative terms) or potency. We have constructed a selectivity-oriented test system that consists of 26 compound selectivity sets against 13 individual targets belonging to three distinct families and contains a total of 558 selective compounds. The targets were chosen because of pharmaceutical relevance and the availability of suitable ligands, privileged structural motifs and/or target structure information. Compound selectivity sets were characterized by structural diversity, chemical scaffold and selectivity range analysis. The test system is made freely available and should be useful for the development of computational approaches in chemical biology.