Fig. (1).

Schematic representation of the chemical library screen. A, The Torrey Pines Institute for Molecular Studies scaffold library approach starts with >30 million compounds that are organized by 68 core scaffolds with 2,000 – 700,000 different compounds per scaffold. B, A lead scaffold is selected for the positional scanning screen. C, All of the compounds in the positional scanning screen contain the same core scaffold structure and are organized by the R-groups at each position. Each of the plates contains the same compounds organized by the different R-group position to determine if a particular functional group is optimal at one of the positions. The positional scanning library screened in this study contained 110 positional scanning samples that each comprise of 1,000 – 2,000 individual compounds for a total diversity of 45864 individual compounds. D, The selectivity for the different R-groups is predicted for each position based on the positional scanning results. In this study, 48 individual compounds were synthesized. E, Of the 48 individual compounds synthesized ten were selected for further analysis in additional assays. In total 226 samples were tested; 68 Scaffolds, 110 positional scanning scaffolds, 48 individual compounds.