Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries

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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 (DOS) libraries. Herein we report a comprehensive characterization of 15 bis-diazacyclic combinatorial libraries obtained through libraries from libraries, which is a DOS 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 DOS libraries with existing drugs or any other compound collection.

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  • Increased_diversity.pdf

    Rights statement: This is the pre-peer reviewed version of the following article: López-Vallejo, Fabian; Nefzi, Adel; Bender, Andreas; Owen, John R.; Nabney, Ian T.; Houghten, Richard A. and Medina-Franco, Jose L. Medina (2011). Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries. Chemical Biology and Drug Design, 77 (5), pp. 328-342, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/j.1747-0285.2011.01100.x/abstract

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Original languageEnglish
Pages (from-to)328-342
Number of pages15
JournalChemical Biology and Drug Design
Volume77
Issue5
DOIs
StatePublished - May 2011

Bibliographic note

This is the pre-peer reviewed version of the following article: López-Vallejo, Fabian; Nefzi, Adel; Bender, Andreas; Owen, John R.; Nabney, Ian T.; Houghten, Richard A. and Medina-Franco, Jose L. Medina (2011). Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries. Chemical Biology and Drug Design, 77 (5), pp. 328-342, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/j.1747-0285.2011.01100.x/abstract

    Keywords

  • chemical space, combinatorial chemistry, drugs, diversity-oriented synthesis, molecular diversity, visualization

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