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 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

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)491-500
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Volume23
Issue number8
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

Glucosylceramidase
Membrane Proteins
Ligands
fragments
proteins
Proteins
ligands
Crystal structure
Gaucher Disease
Drug Design
Computational methods
Protein Binding
Free energy
Parkinson Disease
Parkinson disease
crystal structure
Pharmacology
drugs
Pharmaceutical Preparations
free energy

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications

Cite this

Detection of ligand binding hot spots on protein surfaces via fragment-based methods : Application to DJ-1 and glucocerebrosidase. / Landon, Melissa R.; Lieberman, Raquel L.; Hoang, Quyen; Ju, Shulin; Caaveiro, Jose M M; Orwig, Susan D.; Kozakov, Dima; Brenke, Ryan; Chuang, Gwo Yu; Beglov, Dmitry; Vajda, Sandor; Petsko, Gregory A.; Ringe, Dagmar.

In: Journal of Computer-Aided Molecular Design, Vol. 23, No. 8, 2009, p. 491-500.

Research output: Contribution to journalArticle

Landon, MR, Lieberman, RL, Hoang, Q, Ju, S, Caaveiro, JMM, Orwig, SD, Kozakov, D, Brenke, R, Chuang, GY, Beglov, D, Vajda, S, Petsko, GA & Ringe, D 2009, '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, vol. 23, no. 8, pp. 491-500. https://doi.org/10.1007/s10822-009-9283-2
Landon, Melissa R. ; Lieberman, Raquel L. ; Hoang, Quyen ; Ju, Shulin ; Caaveiro, Jose M M ; Orwig, Susan D. ; Kozakov, Dima ; Brenke, Ryan ; Chuang, Gwo Yu ; Beglov, Dmitry ; Vajda, Sandor ; Petsko, Gregory A. ; Ringe, Dagmar. / Detection of ligand binding hot spots on protein surfaces via fragment-based methods : Application to DJ-1 and glucocerebrosidase. In: Journal of Computer-Aided Molecular Design. 2009 ; Vol. 23, No. 8. pp. 491-500.
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