Drug Design and Synthesis Core

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ABSTRACT The Drug Design and Synthesis Core (DDSC), a key component of the COBRE Center for Targeted Therapeutics (CTT), will enable current and future COBRE faculty to access expertise in assessing the feasibility of developing a chemical biology probe and/or drug candidate for a particular target, provide access to equipment and expertise in synthetic medicinal chemistry, computational chemistry and lastly in the development and validation of binding and functional assays. These services will allow biologists, biochemists and pharmacologists access to key functional molecules that they require for drug target validation, studies using a chemical biology probe and furthermore in preclinical drug development studies. Towards this goal, the Core will pursue the following specific aims: Aim 1. Drug Target Feasibility Assessment: The DDSC will provide a detailed evaluation of targets in terms of druggability, i.e. the feasibility of chemically modulating functional activity of the target of interest or downstream activity through protein-protein interactions. Aim 2. Synthetic Medicinal Chemistry for Hit Expansion and Lead Optimization: The DDSC will provide synthetic chemistry support for the projects described in this COBRE application by sourcing known and commercially available ligands (for use as chemical biology probes), by designing synthesis routes for potential target molecules identified through in vitro or in silico screening (Aim 3) and by designing chemical libraries of initial hits for hit expansion (structure-activity relationships) and lead optimization purposes. Aim 3. Structure and/or Ligand Based Drug Design for hit identification, hit expansion and lead optimization: The computational chemistry facility within the DDSC will provide support for 1) in silico screens to identify chemical starting points (hits) for desired biological targets. 2) Structure-guided lead optimization through computational analysis of identified hits (and structurally related inactives) facilitating rational design of specific analogues and chemical libraries to improve target affinity, selectivity and to impart drug-like physicochemical properties. Aim 4. In vitro binding and functional assay development: The DDSC will provide expertise and resources for development of binding and functional assays that will serve in the hit identification and lead optimization stages. The developed assays will be used for different types of screenings, including high-throughput screening (HTS) at the collaborating HTS facility. Through knowledge of a target’s ligandable sites including sites of protein-protein interactions, in vitro binding assays will be developed that can be used for determining the affinity of compounds discovered using computational screening and also for miniaturization in high- throughput testing. Assay development will also be supported by the DDSC through the synthesis of the required probes and tracer molecules such as biotin or fluorescein linked ligands for a particular drug target.