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

研究成果: Contribution to journalArticle

68 引用 (Scopus)

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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.

元の言語英語
ページ(範囲)491-500
ページ数10
ジャーナルJournal of Computer-Aided Molecular Design
23
発行部数8
DOI
出版物ステータス出版済み - 2009

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