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Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase

Journal of Computer-Aided Molecular Design volume 23, pages 491–500 (2009)Cite this article

Abstract

The identification of hot spots, i.e., binding regions that contribute substantially to the free energy of ligand binding, is a critical step for structure-based drug design. Here we present the application of two fragment-based methods to the detection of hot spots for DJ-1 and glucocerebrosidase (GCase), targets for the development of therapeutics for Parkinson’s and Gaucher’s diseases, respectively. While the structures of these two proteins are known, binding information is lacking. In this study we employ the experimental multiple solvent crystal structures (MSCS) method and computational fragment mapping (FTMap) to identify regions suitable for the development of pharmacological chaperones for DJ-1 and GCase. Comparison of data derived via MSCS and FTMap also shows that FTMap, a computational method for the identification of fragment binding hot spots, is an accurate and robust alternative to the performance of expensive and difficult crystallographic experiments.

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Acknowledgments

M. R. L was supported by grant F32NS061415 from the National Institute of Neurological Disorders and Stroke (NINDS). Research performed in the laboratory of S. V. was supported by grant GM064700 from the National Institutes of Health (NIH). R. L. L. was supported by fellowship F32AG027647 from the National Institutes of Health. G. A. P. is a Duvoisin fellow of the American Parkinson’s Disease Association. G. A. P. and D. R. are recipients of an award from the McKnight Endowment Fund for Neuroscience. Parkinson’s Disease work at Brandeis University was initiated with generous support from the Ellison Medical Foundation. Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory (SSRL) and the Advanced Photo Source (APS), national user facilities operated on behalf of the US Department of Energy, Office of Basic Energy Sciences. Work performed at FM/CA-CAT at APS has been funded in whole or in part with federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science (Y1-GM-1104). We would also like to thank Amicus Therapeutics for their generous support.

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Author notes

  1. Jose M. M. Caaveiro

    Present address: Physical Biochemistry Laboratory, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

Authors and Affiliations

  1. Department of Biochemistry, Rosenstiel Basic Medical Sciences Center, Brandeis University, 415 South Street MS 029, Waltham, MA, 02454, USA

    Melissa R. Landon, Quyen Q. Hoang, Shulin Ju, Jose M. M. Caaveiro, Gregory A. Petsko & Dagmar Ringe

  2. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA

    Raquel L. Lieberman & Susan D. Orwig

  3. Department of Biomedical Engineering, Boston University, Boston, MA, USA

    Dima Kozakov, Gwo-Yu Chuang, Dmitry Beglov & Sandor Vajda

  4. Bioinformatics Graduate Program, Boston University, Boston, MA, USA

    Ryan Brenke

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  1. Melissa R. Landon
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Correspondence to Dagmar Ringe.

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Landon, M.R., Lieberman, R.L., Hoang, Q.Q. et al. Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase. J Comput Aided Mol Des 23, 491–500 (2009). https://doi.org/10.1007/s10822-009-9283-2

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  • DOI: https://doi.org/10.1007/s10822-009-9283-2

Keywords

  • Fragment-based drug design
  • Structure-based drug design
  • Hot spot identification
  • DJ-1
  • Glucocerebrosidase
  • Parkinson’s disease
  • Gaucher’s disease
  • Pharmacological chaperones