- Computer-aided drug design of small molecules inhibiting the XPF-ERCC1 dimerization
We are part of the Alberta DNA Repair Consortium (Aldrecon), a large-scale provincial initiative aiming to bring new cancer therapies targeting the DNA repair mechanisms in cancer cells from bench to clinic. The XPF-ERCC1 enzyme is an essential endonuclease for various DNA repair pathways, which in cancer cells are involved in counteracting the DNA damaging effect of platinum-based chemotherapy and radiotherapy. Inhibiting its action in cancer cells can, therefore, enhance the impact of cancer therapies, resulting in lower dosages and drug resistance effect. We are developing and applying in silico drug design methods to identify and rational modify new inhibitors for the XPF-ERCC1 dimerization, required for the activity of the endonuclease. The identified hits are purchased or synthesized and then tested in biochemical/biological assays and animal models at the labs involved in the Aldrecon project.
- Electrical signalling in cells
– with collaborator Dr. Michael Levin, Tufts University
Bioelectrical signaling in non-neural tissues, produced via ion channels and pumps in the cell membrane, regulate important processes like cell proliferation, migration, differentiation, embryogenesis and regeneration. In addition, these signals have important biomedical applications, for example, in regenerative medicine and tumor suppression. This project aims to address how bioelectrical signals can be modified through the use of ion channel drugs to open or close channels to obtained the desired bioelectric state. A physiological simulator, BioElectric Tissue Simulation Engine (BETSE), has been created by collaborator Alexis Pietak. This program predicts bioelectric patterns and their spatio-temporal dynamics by modeling ion channel and gap junction activity and tracking changes to the ion concentration and transmembrane potential. Work in the Tuszynski group has focused on two aspects: (1) Refining the BETSE model; and (2) building databases of gene expression, ion channel proteins and compounds known to target ion channels. The later can be integrated with BETSE to identify ideal drug combinations that create the desired bioelectrical signals in tissues of interest. Work in the Levin group will use cell experiments to verify the results predicted by BETSE. Our goal is to be able to create drug cocktails that will interact with ion transport proteins to create a specific bioelectric outcome that can be exploited as a bioelectric intervention for control of morphogenesis, regeneration and cancer development.
- Pathology of a-synuclein in neurodegenerative disease
– with collaborator Dr. Michael Woodside, University of Alberta
Intrinsically disordered proteins adopt unstructured states under physiological conditions, but are notoriously difficult to study by conventional structure determination methods. Furthermore, the misfolding of many of these proteins are implicated with a variety of disease. For example, the intrinsically disordered protein a-synuclein may adopt a rare, ordered state that leads to aggregation, a key feature of Parkinson’s Disease and Lewy Body Dementia. The earliest oligomers are thought to be the most toxic agent in the disease, which makes these early states ideal protein targets for drugs. Unfortunately, very little is known about the structure adopted by a-synuclein in these early oligomers. Our work aims to address this challenge by combining experiments (single molecule force spectroscopy, fluorescence correlation spectroscopy) and computations (Monte Carlo simulations, Monte Carlo pulling) in order to obtain structural models and kinetic information about the earliest stages of aggregate formation. Obtaining structural models will provide us with protein targets, where computational screening may be used to identify new drug candidates that interfere with oligomerization. The ability of these compounds to inhibit oligomerization will then be tested in experimental assays. This process will be continuously refined to identify new compounds that are effective inhibitors of the formation of small a-synuclein oligomers, which can be further developed as drugs.