Journal of Computer-Aided Molecular Design

, Volume 23, Issue 8, pp 491–500 | Cite as

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

  • Melissa R. Landon
  • Raquel L. Lieberman
  • Quyen Q. Hoang
  • Shulin Ju
  • Jose M. M. Caaveiro
  • Susan D. Orwig
  • Dima Kozakov
  • Ryan Brenke
  • Gwo-Yu Chuang
  • Dmitry Beglov
  • Sandor Vajda
  • Gregory A. Petsko
  • Dagmar RingeEmail author


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.


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



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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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Melissa R. Landon
    • 1
  • Raquel L. Lieberman
    • 2
  • Quyen Q. Hoang
    • 1
  • Shulin Ju
    • 1
  • Jose M. M. Caaveiro
    • 1
    • 5
  • Susan D. Orwig
    • 2
  • Dima Kozakov
    • 3
  • Ryan Brenke
    • 4
  • Gwo-Yu Chuang
    • 3
  • Dmitry Beglov
    • 3
  • Sandor Vajda
    • 3
  • Gregory A. Petsko
    • 1
  • Dagmar Ringe
    • 1
    Email author
  1. 1.Department of Biochemistry, Rosenstiel Basic Medical Sciences CenterBrandeis UniversityWalthamUSA
  2. 2.School of Chemistry and BiochemistryGeorgia Institute of TechnologyAtlantaUSA
  3. 3.Department of Biomedical EngineeringBoston UniversityBostonUSA
  4. 4.Bioinformatics Graduate ProgramBoston UniversityBostonUSA
  5. 5.Physical Biochemistry Laboratory, Department of Medical Genome Sciences, Graduate School of Frontier SciencesThe University of TokyoTokyoJapan

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