Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase |
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Authors: | 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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Institution: | 1. Department of Biochemistry, Rosenstiel Basic Medical Sciences Center, Brandeis University, 415 South Street MS 029, Waltham, MA, 02454, USA 2. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA 5. Physical Biochemistry Laboratory, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan 3. Department of Biomedical Engineering, Boston University, Boston, MA, USA 4. Bioinformatics Graduate Program, Boston University, Boston, MA, USA
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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. |
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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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