Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning.
Correy, G.J., Rachman, M.M., Togo, T., Gahbauer, S., Doruk, Y.U., Stevens, M.G.V., Jaishankar, P., Kelley, B., Goldman, B., Schmidt, M., Kramer, T., Radchenko, D.S., Moroz, Y.S., Ashworth, A., Riley, P., Shoichet, B.K., Renslo, A.R., Walters, W.P., Fraser, J.S.(2025) Sci Adv 11: eads7187-eads7187
- PubMed: 40435250 
- DOI: https://doi.org/10.1126/sciadv.ads7187
- Primary Citation of Related Structures:  
7HCB, 7HCC, 7HCD, 7HCE, 7HCF, 7HCG, 7HCH, 7HCI, 7HCJ, 7HCK, 7HCL, 7HCM, 7HCN, 7HCO, 7HCP, 7HCQ, 7HCR, 7HCS, 7HCT, 7HCU, 7HCV, 7HCW, 7HCX, 7HCY, 7HCZ, 7HD0, 7HD1, 7HD2, 7HD3, 7HD4, 7HD5, 7HD6, 7HD7, 7HD8, 7HD9, 7HDA, 7HDB, 7HDC, 7HDD, 7HDE, 7HDF, 7HDG, 7HDH, 7HDI, 7HDJ, 7HDK, 7HDL, 7HDM, 7HDN, 7HDO - PubMed Abstract: 
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 ¦̀M median inhibitory concentration (IC 50 ). We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent binding with a 220 ¦̀M IC 50 . Further optimization led to analogs with IC 50 values better than 10 ¦̀M. This lead series has improved membrane permeability and is poised for optimization. FrankenROCS is a scalable method for fragment linking to exploit synthesis-on-demand libraries.
Organizational Affiliation: 
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.