Determination of the 3D Structure of Biologically Active Small Molecules in Complex with DJ-1
Rapid Response Innovation Awards, 2013
Objective/Rationale: † † † † † ††
Mutations in the DJ-1 gene have been associated with Parkinsonís disease onset. This project will determine the 3D structure of the DJ-1 protein in complex with novel drug-like compounds. These compounds were identified by a unique DJ-1 binding screen and are active in protecting from oxidative stress in dopaminergic neurons. The insights from the 3D structure of the complex will enable the knowledge of the mechanism of action of these compounds.
Project Description: † † † † † ††
The ability of newly synthesized compounds to bind to DJ-1 will be assessed, and the 3D structure of the DJ-1 protein in complex with biologically active novel small molecules will be solved by using x-ray crystallography.†
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
The overarching goal is to develop a small molecule therapeutic for Parkinsonís disease by targeting DJ-1. The 3D view of the binding mode of novel compounds to the DJ-1 protein will enable structure-based optimization of these compounds potentially into pre-clinical therapeutic candidates. †
Anticipated Outcome: † † † † †
Researchers anticipate this project will provide information about the binding site of the compounds on DJ-1 and their intermolecular interactions with the protein, which will provide important structural and biophysical insight into the therapeutic targeting of DJ-1 for Parkinsonís disease and related disorders.
Chief Executive Officer at Gardedam Therapeutics
Location: Mclean, Virginia, United States
Professor at Purdue University
Location: West Lafayette, Indiana, United States