Defining Privileged Reagents Using Subsimilarity Comparison

We have developed a new method for assigning a drug-like score to reagents. This algorithm uses topological
torsion (TT) 2D descriptors to compute the subsimilarity of any given reagent to a substructural element of
any compound in the CMC. The utility of this approach is demonstrated by scoring a test set of reagents
derived from the “Comprehensive Survey of Combinatorial Library Synthesis:  2000” (J. Comb. Chem.).
R-groups were extracted from the most-active compounds found in each of the reviewed libraries, and the
distribution of the subsimilarity scores for these monomers were compared to the ACD. This comparison
showed a dramatic shift in the distribution of the JCC R-group subset toward higher subsimilarity scores in
comparison to the entire ACD database. The ACD was also used to examine the relationship between
molecular weight and various subsimilarity scoring algorithms. This analysis was used to derive a subsimilarity
score that is less biased by molecular weight.