Size Doesn't Matter: Scaffold Diversity, Shape Diversity and Biological Activity of Combinatorial Libraries

Abstract

Among questions of significant interest to the pharmaceutical industry are the relative merits of screening numerous libraries of moderate size (<5000 members) comprising many different scaffold structures, versus screening numerically larger libraries (>100,000 members) of a limited selection of chemotypes. Using a newly developed computational method to assess the diversity in molecular shape associated with different compound sets, we have shown that single-scaffold libraries, irrespective of their size, are restricted to a limited range of molecular shapes, whereas collections of several small libraries around distinct chemical scaffolds can produce a higher degree of shape diversity. A comparison of the molecular shape distribution patterns associated with different MDDR (MDL® Drug Data Report) subsets of known biological activities 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. In order to cope with the challenge of assembling a portfolio of small libraries around various central scaffolds in a reasonable amount of time, the combinatorial chemist must now, more than ever, seek to optimize the synthetic outcome with respect to the efforts in terms of chemistry set-up and validation.