Core B – Antiviral Drug Discovery and Development ABSTRACT The Midwest AViDD center is comprised of multidisciplinary teams supported by highly integrated cores to identify and develop orally available drugs to address the immediate threat of Severe Acute Respiratory Syndrome CoV-2 (SARS2), as well as provide antiviral drug candidates targeting viruses with the potential for pandemics. Core-B is the entry portal into the drug development pipeline, serving as the screening core for the initial discovery of bioactive chemical matter that provides the basis for early antiviral drug discovery and its development. To establish a comprehensive screening program within Core-B, a multidisciplinary approach will be employed to facilitate parallel small molecule screening efforts using traditional ultra-High Throughput Screening (uHTS) at Scripps Research-Florida (SRMSC) under Dr. Scampavia; DNA-Encoded Chemistry Technology (DEC-Tec) at the Baylor School of Medicine under Dr. Young; and Computational in silico Virtual Screening (VS) under investigators Dr. Head-Gordon (UC Berkeley) and Dr. Amaro (UCSD). This Core-B program is unique in its approach having integrated traditional pharmaceutical HTS and Virtual Screening (VS) methods with emerging Computational and DNA-enable library screening methods to provide a cost-effective and comprehensive means of exploration into novel chemical space for drug leads. It is envisioned that the three screening components to Core B (uHTS, DEC-Tec, Computational/VS) will identify lead series through iterative cycles of evaluation and refinement using their respective state-of-the-art screening technologies, structure-based design, and with refinement made possible with medicinal chemistry SAR guidance (Core-C). Core-B duties will also provide integrated compound management services, where SRMSC will serve as the central repository of acquired chemical lead matter derived from its Core-B investigators and Core-C medicinal chemistry efforts. Compound management will include database registration of chemical matter into Core-A cloud-based CDDVault and support for the integration of cheminformatic and bioinformatic data. Compound management will provide storage, chemical formatting, and allocation of chemical leads to support ongoing projects and Cores. The discovery of antiviral candidates requires effective and integrated collaborations leveraging the highly experienced expertise of core-B investigators to enable the identification and triage of validated hit series and support their optimization through Cores C-D and project investigators into promising antiviral drug leads suitable for DMPK and in vivo animal studies.