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Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

Journal of Computer-Aided Molecular Design volume 25, pages 621–636 (2011)Cite this article

Abstract

Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM–mM hits and the uniqueness of hits at weak binding affinities for these targets.

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Acknowledgments

Tudor Oprea for the SMCM program; Marty Marx, Kim Daoust, James Forman and Bob Mecca for RI support; Parag Sahasrabudhe, Hong Wang, Diana Omechinsky, Kris Borzilleri, Cathy Moore and Jiangli Yan for NMR support; Gaia Paolini and Zhengwei Peng for computational input; Bob Chambers, Kim Matus, Kyle Blair, Lisa Thomasco, Jan Snape, Shirell Gray, Jola Nowakowski, Maria Anhalt, Steve Curioso, Craig Hines, Diane Johnson, Bernadette Udasco, Jason Harraden, Erin Cyr, Betsy Poe, Monica Gorny, Elizabeth Mostowy, Holly McKeith, Jed Morris, Tim Britt, Frank Girardi, C.K. Chan for library preparation and sample logistics support; G. Tim Benson, Mike Clark, Tony Wood, Ron Wester and Suvit Thaisrivongs and Alan Mathiowetz for initiative support.

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Authors and Affiliations

  1. Pfizer Global Research and Development (PGRD), Eastern Point Rd, Groton, CT, 06340, USA

    Wan F. Lau, Jane M. Withka, David Hepworth, Thomas V. Magee, Gregory A. Bakken, Michael D. Miller, Zachary S. Hendsch & Venkataraman Thanabal

  2. PTC Therapeutic, Inc., 100 Corporate Court, South Plainfield, NJ, 07080, USA

    Yuhua J. Du

  3. Pfizer Global Research and Development (PGRD), Saint Louis, MO, USA

    Steve A. Kolodziej

  4. Pfizer Global Research and Development (PGRD), Cambridge, MA, USA

    Li Xing & Maura E. Charlton

  5. Pfizer Global Research and Development (PGRD), La Jolla, CA, USA

    Qiyue Hu, Lakshmi S. Narasimhan & Robert Love

  6. Pfizer Global Research and Development (PGRD), Sandwich, UK

    Samantha Hughes & James E. Mills

  7. Accelrys Ltd, 334 Cambridge Science Park, Cambridge, CB4 0WN, UK

    Willem P. van Hoorn

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  1. Wan F. Lau
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  2. Jane M. Withka
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  11. Li Xing
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  13. Lakshmi S. Narasimhan
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Corresponding authors

Correspondence to Wan F. Lau or Jane M. Withka.

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Lau, W.F., Withka, J.M., Hepworth, D. et al. Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics. J Comput Aided Mol Des 25, 621–636 (2011). https://doi.org/10.1007/s10822-011-9434-0

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  • DOI: https://doi.org/10.1007/s10822-011-9434-0

Keywords

  • Fragment screening
  • Fragment based drug design
  • Library design
  • Chemical diversity
  • Chemical space