DNA repair is a set of important cellular processes which identify and restore damage to the cellular DNA molecules encoding the genome. Failure of proper DNA repair is associated with many forms of disease, among them neurodegenerative disorders such as Alzheimer's disease. Since neurons are constantly cycling cells, their metabolic demand is much higher when compared to normal non-cycling cells. As a result of this, they build up a high number of reactive oxygen species which tend to cause DNA damage. Patients with neurodegenerative disorders often exhibit elevated levels of DNA damage. Thus one possible intervention could be activated DNA repair, however no clinically approved drugs are available for this purpose. In previous research we found that the neuronal protein cyclin A2 is a regulator of neuronal genomic stability and DNA repair, while inhibition of cyclin A2 leads to learning and memory deficits in test animals. The structure of cyclin A2 is known but no small molecule binders have been reported. The main objective of this proposal is to use computational methods to find a set of small molecules that bind to cyclin A2 and can act as activators (agonists). We will use biochemical methods to verify our computational predictions. The proposed research is structured into two main stages. First, we will thoroughly sample the dynamics of the cyclin A2 protein and identify potential drug binding sites (Aim I). Subsequently, we will perform a structure-based computational screening of large virtual compound databases to identify potential cyclin A2 agonists, whose activity will be verified using in vitro biochemical and cell-based assays (Aim II). The proposed research combines aspects of computational chemistry, biophysics and pharmacology.
The proposed research is relevant to public health because it will result in the discovery of new agonists that could promote neuronal repair. This new knowledge will ultimately serve as the framework upon which improved therapies for neurodegenerative disease patients are based. Therefore, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will ultimately help reduce the burdens of human disease.
