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Adventures in Small Molecule Fragment Screening by X-ray Crystallography

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Multifaceted Roles of Crystallography in Modern Drug Discovery

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Abstract

Since its conception in the early 1990s, fragment-based drug discovery (FBDD) has become established as a powerful tool for identifying new, chemically tractable pharmacophores. Unlike traditional methods that focus primarily on initial potency, FBDD stresses efficiency of binding and exploration of a highly diverse chemical space. Small fragment library sizes (∼1,000 compounds) and the weak binding affinity of fragments have spurred the use of biophysical methods not readily applicable to screening of traditional compound libraries (greater than 100,000 compounds). X-ray crystallography is a powerful, yet under-appreciated, biophysical method for systematic identification of small molecule binding and discovery of potential inhibitory sites in a macromolecular target. Indeed, due to tremendous improvements in methodologies and technologies involved in X-ray data collection and analysis, it is now possible to collect data on a complete fragment library for a given macromolecular target during a single trip to a current generation synchrotron. Here we highlight some key insights and innovations learned from fragment screening campaigns targeting influenza and HIV-1 polymerases.

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Acknowledgement

EA is grateful to the National Institutes of Health for support from grants R37 AI027690 (MERIT Award) and P50 GM103368. We also thank our collaborators in RT studies, both past and present.

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Authors and Affiliations

  1. Center for Advanced Biotechnology and Medicine, Rutgers University, 679 Hoes Lane West, Piscataway, NJ, 08854, USA

    Joseph D. Bauman, Disha Patel & Eddy Arnold

Authors
  1. Joseph D. Bauman
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  2. Disha Patel
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  3. Eddy Arnold
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Corresponding authors

Correspondence to Joseph D. Bauman or Eddy Arnold .

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Editors and Affiliations

  1. Structural Chemistry Department, Merck & Co, Inc., Kenilworth, New Jersey, USA

    Giovanna Scapin

  2. Center for Advanced Biotechnology and Medicine, and Rutgers University, Piscataway, New Jersey, USA

    Disha Patel

  3. Center for Advanced Biotechnology and Medicine, and Rutgers University, Piscataway, New Jersey, USA

    Eddy Arnold

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Bauman, J.D., Patel, D., Arnold, E. (2015). Adventures in Small Molecule Fragment Screening by X-ray Crystallography. In: Scapin, G., Patel, D., Arnold, E. (eds) Multifaceted Roles of Crystallography in Modern Drug Discovery. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9719-1_15

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