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

Fabian López-Vallejo, Adel Nefzi, Andreas Bender, John R. Owen, Ian T. Nabney, Richard A. Houghten, Jose L. Medina Medina-Franco

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)328-342
Number of pages15
JournalChemical Biology and Drug Design
Volume77
Issue number5
DOIs
Publication statusPublished - May 2011

Fingerprint

Libraries
Small Molecule Libraries
Dermatoglyphics
Pharmaceutical Preparations
Thiourea
Drug Discovery
Molecules

Bibliographical 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

Cite this

López-Vallejo, F., Nefzi, A., Bender, A., Owen, J. R., Nabney, I. T., Houghten, R. A., & Medina-Franco, J. L. M. (2011). Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries. Chemical Biology and Drug Design, 77(5), 328-342. https://doi.org/10.1111/j.1747-0285.2011.01100.x
López-Vallejo, Fabian ; Nefzi, Adel ; Bender, Andreas ; Owen, John R. ; Nabney, Ian T. ; Houghten, Richard A. ; Medina-Franco, Jose L. Medina. / Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries. In: Chemical Biology and Drug Design. 2011 ; Vol. 77, No. 5. pp. 328-342.
@article{5c1f6ff45b9b400082cc6d5d2ef8cedc,
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 (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.",
keywords = "chemical space, combinatorial chemistry, drugs, diversity-oriented synthesis, molecular diversity, visualization",
author = "Fabian L{\'o}pez-Vallejo and Adel Nefzi and Andreas Bender and Owen, {John R.} and Nabney, {Ian T.} and Houghten, {Richard A.} and Medina-Franco, {Jose L. Medina}",
note = "This is the pre-peer reviewed version of the following article: L{\'o}pez-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",
year = "2011",
month = "5",
doi = "10.1111/j.1747-0285.2011.01100.x",
language = "English",
volume = "77",
pages = "328--342",
journal = "Chemical Biology and Drug Design",
issn = "1747-0277",
publisher = "Blackwell",
number = "5",

}

López-Vallejo, F, Nefzi, A, Bender, A, Owen, JR, Nabney, IT, Houghten, RA & Medina-Franco, JLM 2011, 'Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries', Chemical Biology and Drug Design, vol. 77, no. 5, pp. 328-342. https://doi.org/10.1111/j.1747-0285.2011.01100.x

Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries. / López-Vallejo, Fabian; Nefzi, Adel; Bender, Andreas; Owen, John R.; Nabney, Ian T.; Houghten, Richard A.; Medina-Franco, Jose L. Medina.

In: Chemical Biology and Drug Design, Vol. 77, No. 5, 05.2011, p. 328-342.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increased diversity of libraries from libraries: chemoinformatic analysis of bis-diazacyclic libraries

AU - López-Vallejo, Fabian

AU - Nefzi, Adel

AU - Bender, Andreas

AU - Owen, John R.

AU - Nabney, Ian T.

AU - Houghten, Richard A.

AU - Medina-Franco, Jose L. Medina

N1 - 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

PY - 2011/5

Y1 - 2011/5

N2 - 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.

AB - 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.

KW - chemical space

KW - combinatorial chemistry

KW - drugs

KW - diversity-oriented synthesis

KW - molecular diversity

KW - visualization

UR - http://www.scopus.com/inward/record.url?scp=79954626779&partnerID=8YFLogxK

U2 - 10.1111/j.1747-0285.2011.01100.x

DO - 10.1111/j.1747-0285.2011.01100.x

M3 - Article

VL - 77

SP - 328

EP - 342

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

IS - 5

ER -