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Design of a Fragment Library that maximally represents available chemical space

Journal of Computer-Aided Molecular Design volume 25, pages 611–620 (2011)Cite this article

Abstract

Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resulting Fragment Sets have been characterised on the basis of computed physico-chemical properties and their similarity to the Input Libraries. A method that iteratively identifies fragments with the maximum number of similar compounds in the Input Library (Nearest Neighbours) produces the most diverse library. This approach could increase the success of experimental ligand discovery projects, by providing fragments that can be progressed rapidly to larger compounds through access to available similar compounds (known as SAR by Catalog).

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Acknowledgments

We thank Accelrys for providing access to software and Eddy Van de Water of Accelrys for specific technical support. We are grateful to Hans Briem and Judith Günther from Bayer and Steve Roughley and James Davidson of Vernalis for helpful discussions. The work was supported by a grant from the Biotechnology and Biological Sciences Research Council, JL by a fellowship from the Swedish Pharmaceutical Society and MNS was partially supported by the Wild fund.

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Authors and Affiliations

  1. YSBL, Chemistry Department, University of York, Heslington, York, YO10 5DD, UK

    M. N. Schulz, J. Landström, K. Bright & R. E. Hubbard

  2. HYMS, University of York, Heslington, York, YO10 5DD, UK

    R. E. Hubbard

  3. Vernalis (R&D) Ltd, Granta Park, Abington, Cambridge, CB21 6GB, UK

    R. E. Hubbard

Authors
  1. M. N. Schulz
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  2. J. Landström
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  3. K. Bright
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  4. R. E. Hubbard
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Correspondence to R. E. Hubbard.

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Schulz, M.N., Landström, J., Bright, K. et al. Design of a Fragment Library that maximally represents available chemical space. J Comput Aided Mol Des 25, 611–620 (2011). https://doi.org/10.1007/s10822-011-9461-x

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Keywords

  • Fragment-based ligand discovery
  • Library design
  • SAR by catalog
  • Nearest neighbours