Molecular Shape Diversity of Combinatorial Libraries:  A Prerequisite for Broad Bioactivity

A computational method to rapidly assess and visualize the diversity in molecular shape associated with a given compound set has been developed. Normalized ratios of principal moments of inertia are plotted into two-dimensional triangular graphs and then used to compare the shape space covered by different compound sets, such as combinatorial libraries of varying size and composition. We have further developed a computational method to analyze interset similarity in terms of shape space coverage, which allows the shape redundancy between the different subsets of a given compound collection to be analyzed in a quantitative way. The shape space coverage has been found to originate mainly from the nature and the 3D-geometry (but not the size) of the central scaffold, while the number and nature of the peripheral substituents and conformational aspects were shown to be of minor importance. Substantial shape space coverage has been correlated with broad biological activity by applying the same shape analysis to collections of known bioactive compounds, such as MDDR and the GOLD-set. The aggregate of our results corroborates the intuitive notion that molecular shape is intimately linked to biological activity and that a high degree of shape (hence scaffold) diversity in screening collections will increase the odds of addressing a broad range of biological targets.