During the first year of our project:
• We tested the mode of action of existing compounds and their specificity towards RET and GFRα co-receptors in cultured cells. We found that existing GDNF mimetics do not require the presence of GFRα co-receptors to elicit biological response, but are selective to RET: they do not affect the receptors of other neurotrophic factors. They also fail to stimulate intracellular signalling in the absence of RET.
• We identified several novel potential GDNF mimetics.
• We prepared datasets for generating the first Quantitative Structure Activity Relationship (QSAR) models (computational approach) using Molcode’s proprietary software CODESSA Pro. Molecular structures of approximately 100 small molecules with GDNF mimetic properties were optimized to 3D geometry with lowest conformational energy. The optimized structures were incorporated in CODESSA Pro to calculate molecular descriptors using AM1 parameterization in CMOPAC.
• We transferred technology for rapid identification of GDNF mimetics developed in the University of Helsinki to Molcode Ltd. We confirmed that the method works at Molcode Ltd. premises as efficiently as it does at the University of Helsinki and deposited sufficient quantity of biological materials to analyse improved compounds at Molcode Ltd.
• We started a small pilot study to determine neuroprotective and neurorestorative activity of our compounds in a rat model of PD. Animal experiments were significantly delayed due to the limitation in funding availability. Supplementary support from Parkinson’s UK foundation will allow us to complete the in vivo experiments. Final results are expected to be ready by September 2015.
• One early stage researcher and two experiences researchers participated in the Transfer of Knowledge Program. One scientist from Molcode Ltd. got training in molecular neurosciences and tested existing GDNF mimetics in cell-based assays at the University of Helsinki. Two researchers from University of Helsinki were given training in basics of computational chemistry and prepared dataset for QSAR modelling in Molcode Ltd.
• GDNF mimetics team performed several dissemination and outreach activities to spread results and information about the project. We established project web-page, Facebook project page, presented results of the research to the members of scientific community in Finland and Estonia on several seminars, project and group meetings held in Helsinki and Tartu and organized a project open day for high school students on the premises of University of Helsinki.