Size Doesn't Matter: Scaffold Diversity, Shape Diversity and Biological Activity of Combinatorial Libraries
DOI:
https://doi.org/10.2533/000942903777679253Keywords:
Biological activity, Combinatorial library, Molecular shape, Scaffold, Shape triangle diagramAbstract
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.Downloads
Published
2003-05-01
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Scientific Articles
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Copyright (c) 2003 Swiss Chemical Society
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How to Cite
[1]
W. H. Sauer, M. K. Schwarz, Chimia 2003, 57, 276, DOI: 10.2533/000942903777679253.