The hidden component of size in two-dimensional fragment descriptors: side effects on sampling in bioactive libraries

We have carried out a number of sampling experiments in libraries of bioactive compounds to illustrate how size biases introduced by two-dimensional (2D) fragment distance functions may provide misleading information about the diversity of compound subsets. The number of different biological targets covered by a given subset is used as a measure of bioactive diversity, and it is considered to be the relevant property with which 2D diversity should correlate. Since the nature of the size biases depends on the way in which 2D distance is computed, we investigated three different methods of calculating distance. Use of 1-Tanimoto as a dissimilarity measure leads to the spurious conclusion that collections of structurally small compounds are inherently more diverse than other collections which may cover a broader range of sizes and more biological targets. XOR or squared Euclidean distance, by contrast, shows a preference for subsets of structurally larger compounds, but this does not appear to have as many adverse consequences in terms of target coverage. A simple product of 1-Tanimoto and XOR tends to equalize the opposing size effects of the two component distance functions and leads to a relatively unbiased means of comparing structures. Results here suggest that careful consideration should be given to the way in which chemical structures are compared whenever 2D fragment descriptors are used.