Target enablement

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The success of the Center's drug discovery programs relies on being experimentally fully enabled to support compound development. In the Target Enablement project, we will develop and validate the experimental procedures by producing "Target Enabling Packages" (TEPs). These comprise a set of experimental protocols and outputs that generate the rapid, reliable, full-spectrum readouts that underpin the acceleration of the designmake- test-analyze (DMTA) cycles. TEPs are highly effective enablers of medicinal chemistry on targets and targeting modalities where they can be achieved; nevertheless, frequently they remain incomplete, since they require great effort to assemble from literature and/or trial-and-error experiments; and determined medicinal chemists might manage to progress compound series anyway. However, this conceals the real and opportunity costs of doing so, which includes the synthesis of unnecessary compounds, pursuit of dead-end hypotheses, and poor models of the data. In the Target Enablement project, we propose to generate next generation TEPs that include the reagents and protocols for generating biochemically-behaved, well-crystallizing protein, 3D interaction maps of the binding site(s) from a crystal-based fragment screen, biochemical and biophysical assays and persuasive hit compounds, displaying consistent low micromolar affinity, activity and binding pose, rationalizable across a set of analogues. We will deliver TEPs that are rigorous, effective, and reproducible, by (a) contracting in the established, systematic workflow developed since 2015 at the University of Oxford, and (b) implementing and hardening of recent innovations and new technologies, including methods developed in the wake of the COVID Moonshot and other pandemic-related work. The specific goal of Project 2 is thus to generate next generation TEPs for 10 targets, to drive rapid hit-to-lead progression in Project 3 and thence validation of the antiviral hypothesis by virology and chemical biology. The goal is spread over 4 Aims, with Aim 1 establishing biochemical and crystal structure tractability of all novel targets identified in Project 1. Aim 2 builds on the outputs from Aim 1 and develops the robust crystallization protocols, and orthogonal assays for biochemical activity and biophysical affinity. Aim 3 entails the completion and analyses of the crystallographic fragment screens. Aim 4 finalizes TEPs by validating assays and binding pose with hit compounds derived from observed fragments. In summary, Project 2 combines an established workflow with recent innovations to deliver TEPs that are rigorous, effective and reproducible, providing the foundations for the far-reaching innovations of Project 3 thus ensuring ASAP can deliver on time and on budget. Moreover, TEPs will be promptly published to enable parallel efforts beyond ASAP and increase the overall chances of achieving pandemic preparedness. The project will be delivered by the same team at Diamond Light Source that executed the record-breaking crystallographic (XChem) fragment screen that seeded the COVID Moonshot.