9D6I | pdb_00009d6i

Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning.

(2025) Sci Adv 11: eads7187-eads7187

• PubMed: 40435250 Search on PubMedSearch on PubMed Central
• 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 μM 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 μM IC ₅₀ . Further optimization led to analogs with IC ₅₀ values better than 10 μM. 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.

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Organizational Affiliation: 

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA.