title: Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.
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.
authors.affiliation: Department of Biochemistry, Rosenstiel Basic Medical Sciences Center, Brandeis University, 415 South Street MS 029, Waltham, MA 02454, USA. mlandon@brandeis.edu
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Landon
authors.forename: Raquel L
authors.initials: RL
authors.lastname: Lieberman
authors.forename: Quyen Q
authors.initials: QQ
authors.lastname: Hoang
authors.forename: Shulin
authors.initials: S
authors.lastname: Ju
authors.forename: Jose M M
authors.initials: JM
authors.lastname: Caaveiro
authors.forename: Susan D
authors.initials: SD
authors.lastname: Orwig
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.forename: Ryan
authors.initials: R
authors.lastname: Brenke
authors.forename: Gwo-Yu
authors.initials: GY
authors.lastname: Chuang
authors.forename: Dmitry
authors.initials: D
authors.lastname: Beglov
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D005776:Gaucher Disease / Q000188:drug therapy; D005962:Glucosylceramidase / Q000737:chemistry*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry; D058990:Molecular Targeted Therapy; D015513:Oncogene Proteins / Q000737:chemistry*; D010300:Parkinson Disease / Q000188:drug therapy; D011485:Protein Binding; D011487:Protein Conformation; D000071617:Protein Deglycase DJ-1; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D015513:Oncogene Proteins; D054852:Small Molecule Libraries; D012997:Solvents; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D005962:Glucosylceramidase