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

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67 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
Pages (from-to)491-500
Number of pages10
JournalJournal of Computer-Aided Molecular Design
Volume23
Issue number8
DOIs
Publication statusPublished - Jun 15 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

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

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    Landon, M. R., Lieberman, R. L., Hoang, Q. Q., Ju, S., Caaveiro, J. M. M., Orwig, S. D., Kozakov, D., Brenke, R., Chuang, G. Y., Beglov, D., Vajda, S., Petsko, G. A., & 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, 23(8), 491-500. https://doi.org/10.1007/s10822-009-9283-2