title: Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries.
abstract: Combinatorial libraries continue to play a key role in drug discovery. To increase structural diversity, several experimental methods have been developed. However, limited efforts have been performed so far to quantify the diversity of the broadly used diversity-oriented synthetic libraries. Herein, we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a diversity-oriented synthetic approach. Using MACCS keys, radial and different pharmacophoric fingerprints as well as six molecular properties, it was demonstrated the increased structural and property diversity of the libraries from libraries over the individual libraries. Comparison of the libraries to existing drugs, NCI diversity, and the Molecular Libraries Small Molecule Repository revealed the structural uniqueness of the combinatorial libraries (mean similarity <0.5 for any fingerprint representation). In particular, bis-cyclic thiourea libraries were the most structurally dissimilar to drugs retaining drug-like character in property space. This study represents the first comprehensive quantification of the diversity of libraries from libraries providing a solid quantitative approach to compare and contrast the diversity of diversity-oriented synthetic libraries with existing drugs or any other compound collection.
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: López-Vallejo
authors.forename: Adel
authors.initials: A
authors.lastname: Nefzi
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: John R
authors.initials: JR
authors.lastname: Owen
authors.forename: Ian T
authors.initials: IT
authors.lastname: Nabney
authors.forename: Richard A
authors.initials: RA
authors.lastname: Houghten
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D015195:Drug Design; D048088:Informatics; D008956:Models, Chemical; D012107:Research Design; D054852:Small Molecule Libraries / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D054852:Small Molecule Libraries; D013890:Thiourea