Duncan NRI Damian W. Young, Ph.D.

Research in my laboratory is focused on developing small molecules that can be used to interrogate fundamental and disease-associated biological processes. Our work also centers on the development of human therapeutics for a wide variety of diseases. We use state-of-the-art synthetic organic chemistry to develop small-molecule libraries having different 3-dimensional shapes that can be screened toward modulating a wide swath of protein disease targets. The development of these libraries is guided by a principle that we developed known as Systematic Chemical Diversity (SCD). Through SCD, synthetic chemistry is applied to make controlled and methodical changes in molecular features such as core scaffold, regiochemistry, stereochemistry and appendage substitutions to generate complete matrices of compounds varying in these features. Libraries based on SCD contain comprehensive chemical diversity toward the goal of elucidating specific binders to an array of different types of proteins. Additionally, SCD based libraries provide an extensive amount of Structure-activity relationship (SAR) information directly from the primary screen which enables rapid medicinal chemistry for optimization to a lead compound. We have applied the SCD concept to two established screening paradigms: Fragment-Based Drug Discovery (FBDD) and DNA-Encoded Libraries (DELs).

We are applying these innovative chemical platforms to the development of compounds that promote adult neurogenesis, the development of new neurons beyond development. Adult neurogenesis occurs within the hippocampus of the brain and is involved in processes such as learning, memory, and pattern separation. Impaired neurogenesis is associated with a variety of neurological disorders including major depressive disorder (MDD) and Alzheimer’s disease (AD). The development of pharmacological agents which stimulate adult neurogenesis have the potential to mitigate or eliminate the devastating effects of these diseases. In collaboration with Dr. Mirjana Maletic-Savatic, a pediatric neurologist here at the NRI, we are identifying critical targets involved in regulating adult neurogenesis, and in particular those that can be modulated with small molecules. These targets are being recombinantly expressed and screened against our innovative fragment-based and DNA-encoded libraries. The hits obtained are then efficiently optimized by medicinal chemistry based on a cohort of experiments involving biophysical methods, cell-based studies, organoids, and genetically-modified mouse models of neurogenesis.