Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.
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.
Landon
Melissa R
MR
Department of Biochemistry, Rosenstiel Basic Medical Sciences Center, Brandeis University, 415 South Street MS 029, Waltham, MA 02454, USA. mlandon@brandeis.edu
Lieberman
Raquel L
RL
Hoang
Quyen Q
QQ
Ju
Shulin
S
Caaveiro
Jose M M
JM
Orwig
Susan D
SD
Kozakov
Dima
D
Brenke
Ryan
R
Chuang
Gwo-Yu
GY
Beglov
Dmitry
D
Vajda
Sandor
S
Petsko
Gregory A
GA
Ringe
Dagmar
D
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
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