Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept.
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.
Lisurek
Michael
M
FMP Leibniz Institut für Molekulare Pharmakologie, Robert-Roessle Strasse 10, 13125, Berlin, Germany.
Rupp
Bernd
B
Wichard
Jörg
J
Neuenschwander
Martin
M
von Kries
Jens Peter
JP
Frank
Ronald
R
Rademann
Jörg
J
Kühne
Ronald
R
D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship
D054852:Small Molecule Libraries
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