PROJECT SUMMARY MEDICINAL CHEMISTRY CORE The Emory-Sage-SGC-Jax TREAT-AD Center Medicinal Chemistry (MedChem) Core, led by Dr. Alison Axtman, aims to contribute a key component of Target Enabling Packages (TEPs): a small molecule. At minimum, this small molecule will represent a chemical starting point, validated to bind to its target, in need of further optimization in terms of on-target potency and proteome-wide selectivity. Ideally, this small molecule will prove suitable for optimization by the MedChem Core into a chemical probe that can be shared with the scientific community to interrogate and vet poorly characterized AD protein targets. The track record of the Axtman lab, which is part of the Structural Genomics Consortium (SGC), supports that delivery of chemical probes is both feasible and routinely executed for a variety of targets. Purified protein and assays developed by the Structural Biology Core (StrucBio Core) will enable the MedChem Core to engage in hit discovery, specifically employing DNA-encoded library screening with machine learning (DEL/ML) as part of novel public-private partnerships with XChem and other partners (Open DEL/ML, Aim 1). As part of a unique approach, Open DEL/ML will deposit previously proprietary DEL screening data into the public domain in an ML-enabling format, enabling the community to build models of “hit space” and to use the models to predict commercially-available drug-like hits. Access to purified protein and assays will also facilitate characterization of putative hit compounds within the MedChem Core. The physicochemical properties of these small molecules will be assessed in tandem (Aim 2). Finally, if a confirmed hit has physicochemical properties to support its optimization, the MedChem Core will iteratively design sets of drug-like analogs and evaluate them using a hierarchy of embedded assays to probe target affinity, selectivity, cellular activity, and in vitro ADME properties. Chemical probes that achieve the desired activity in these assays will advance into in vivo assessment of plasma/brain PK and target engagement, and will be considered for advancement to models of AD. Compounds that proceed to hit to probe optimization are likely amongst the best available for a given protein target and thus would be great candidates for inclusion in the AD Informer Set (Aim 3). The specific aims of the MedChem Core are: 1. Hit discovery 2. Hit characterization 3. Hit to probe optimization