Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 23, Issue 8, Pages 491-500Publisher
SPRINGER
DOI: 10.1007/s10822-009-9283-2
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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Funding
- National Institute of Neurological Disorders and Stroke (NINDS) [F32NS061415]
- National Institutes of Health (NIH) [GM064700]
- National Institutes of Health [F32AG027647]
- American Parkinson's Disease Association
- McKnight Endowment Fund
- Ellison Medical Foundation
- US Department of Energy
- National Cancer Institute [Y1-CO-1020]
- National Institute of General Medical Science [Y1-GM-1104]
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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.
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