Open AccessSize Doesn't Matter: Scaffold Diversity, Shape Diversity and Biological Activity of Combinatorial Libraries
Author(s) -
Wolfgang Sauer,
Matthias Schwarz
Publication year - 2003
Publication title -
chimia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.387
H-Index - 55
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/000942903777679253
Subject(s) - diversity (politics) , computer science , scaffold , set (abstract data type) , drug discovery , range (aeronautics) , evolutionary biology , computational biology , biology , biochemical engineering , bioinformatics , engineering , database , programming language , aerospace engineering , sociology , anthropology
Among questions of significant interest to the pharmaceutical industry are the relative merits of screening numerous libraries of moderate size (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.