Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept

作者：Lisurek Michael; Rupp Bernd; Wichard Joerg; Neuenschwander Martin; von Kries Jens Peter; Frank Ronald; Rademann Joerg^*; Kuehne Ronald

来源：Molecular Diversity, 2010, 14(2): 401-408.

DOI：10.1007/s11030-009-9187-z

• Bio informatics
• Drug design
• High throughput screening
• Library design
• Molecular diversity

Success in small molecule screening relies heavily on the preselection of compounds. Here, we present a strategy for the enrichment of chemical libraries with potentially bioactive compounds integrating the collected knowledge of medicinal chemistry. Employing a genetic algorithm, substructures typically occurring in bioactive compounds were identified using the World Drug Index. Availability of compounds containing the selected substructures was analysed in vendor libraries, and the substructure-specific sublibraries were assembled. Compounds containing reactive, undesired functional groups were omitted. Using a diversity filter for both physico-chemical properties and the substructure composition, the compounds of all the sublibraries were ranked. Accordingly, a screening collection of 16,671 compounds was selected. Diversity and chemical space coverage of the collection indicate that it is highly diverse and well-placed in the chemical space spanned by bioactive compounds. Furthermore, secondary assay-validated hits presented in this study show the practical relevance of our library design strategy.

• 出版日期2010-5