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 Ringe
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.

Keywords

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

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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
  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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