Authors: Galen J. Correy, Moira M. Rachman, Takaya Togo, Stefan Gahbauer, Yagmur U. Doruk, Maisie G. V. Stevens, Priyadarshini Jaishankar, Brian Kelley, Brian Goldman, Molly Schmidt, Trevor Kramer, Dmytro S. Radchenko, Yurii S. Moroz, Alan Ashworth, Patrick Riley, Brian K. Shoichet, Adam R. Renslo, W. Patrick Walters, James S. Fraser
Published: 2025-05-28
Source: Full article
The macrodomain of severe acute respiratory syndrome coronavirus 2 nonstructural protein 3 is required for viral pathogenesis and is an emerging antiviral target. We previously performed an x-ray crystallography–based fragment screen and found submicromolar inhibitors by fragment linking. However, these compounds had poor membrane permeability and liabilities that complicated optimization. Here, we developed a shape-based virtual screening pipeline—FrankenROCS. We screened the Enamine high-throughput collection of 2.1 million compounds, selecting 39 compounds for testing, with the most potent binding with a 130 μM median inhibitory concentration (IC