title: Design of chemical libraries with potentially bioactive molecules applying a maximum common substructure concept.
abstract: 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.
authors.affiliation: FMP Leibniz Institut für Molekulare Pharmakologie, Robert-Roessle Strasse 10, 13125, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lisurek
authors.forename: Bernd
authors.initials: B
authors.lastname: Rupp
authors.forename: Jörg
authors.initials: J
authors.lastname: Wichard
authors.forename: Martin
authors.initials: M
authors.lastname: Neuenschwander
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: von Kries
authors.forename: Ronald
authors.initials: R
authors.lastname: Frank
authors.forename: Jörg
authors.initials: J
authors.lastname: Rademann
authors.forename: Ronald
authors.initials: R
authors.lastname: Kühne
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D008958:Models, Molecular; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D054852:Small Molecule Libraries
references.citation: J Mol Graph Model. 2000 Aug-Oct;18(4-5):464-77
references.pmid: 11143563
references.citation: Curr Opin Chem Biol. 2005 Aug;9(4):366-70
references.pmid: 15925537
references.citation: Curr Top Med Chem. 2006;6(1):19-29
references.pmid: 16454755
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17272-7
references.pmid: 16301544
references.citation: J Med Chem. 1996 Jul 19;39(15):2887-93
references.pmid: 8709122
references.citation: Curr Opin Chem Biol. 2006 Aug;10(4):352-6
references.pmid: 16797220
references.citation: J Med Chem. 1988 Dec;31(12):2235-46
references.pmid: 2848124
references.citation: Angew Chem Int Ed Engl. 2008;47(17):3275-8
references.pmid: 18348134
references.citation: ChemMedChem. 2008 Mar;3(3):435-44
references.pmid: 18064617
references.citation: J Med Chem. 2006 Mar 23;49(6):2000-9
references.pmid: 16539387
references.citation: Mol Divers. 2000;5(1):13-24
references.pmid: 11383488
references.citation: J Chem Inf Comput Sci. 2000 May-Jun;40(3):801-9
references.pmid: 10850786
references.citation: J Med Chem. 1992 Jun 12;35(12):2145-54
references.pmid: 1613742
references.citation: Curr Top Med Chem. 2003;3(1):11-23
references.pmid: 12570776
references.citation: J Chem Inf Comput Sci. 2002 Jul-Aug;42(4):912-26
references.pmid: 12132893
references.citation: J Med Chem. 2005 Jan 27;48(2):403-13
references.pmid: 15658854
references.citation: Curr Opin Chem Biol. 2002 Aug;6(4):453-8
references.pmid: 12133720