ABSTRACT MedChem Core D will focus primarily on the delivery of non-nucleoside direct acting antiviral (DAA) leads to the Projects to complement the existing chemical assets in the READDI-AC portfolio. To achieve this goal MedChem Core D will create high-quality non-nucleoside small molecule probes with robust antiviral activity and drug-like pharmacokinetic properties. MedChem Core D is composed of experimental and computational chemists at the US and UK sites of the Structural Genomic Consortium (SGC) who have a track record in developing and sharing freely with the scientific community first-in-class chemical probes and small molecule drug leads. All chemical probes generated by MedChem Core D will be made available to the AViDD centers and the broader research community, unrestricted by IP, to enable deep scientific study of both therapeutic potential as well as breadth of utility of each DAA mechanism. MedChem Core D is particularly well placed to harness the innovation and productivity gains of open science to support its specific aims: Aim 1. Hit Discovery Support: MedChem Core D will support the hit triage of high throughput screens performed by Discovery Core B and seed hit discovery efforts through assembly of target class chemical libraries from structure-based virtual screening (VS) and de novo design approaches. Aim 2. Hit to probe: MedChem Core D will iteratively design sets of drug-like analogs with physiochemical properties consistent with cellular activity. Analogs will be assessed in a hierarchy of assays to address target affinity, cellular activity, ADME properties, and efficacy in virus replication assays. Final probes will be extensively characterized to support their MoA and efficacy and be profiled for in vivo PK to complete a Lead CV. The SGC Open Chemistry Network will be used to provide additional capacity for those targets that yield more than two confirmed hit series. The overall goal of the MedChem Core D is to deliver a minimum of 16 chemical probes with robust anti- viral activity and drug-like properties. These probes will serve as starting points for lead-to-candidate optimization by the Projects.