2. Academic Validation
  3. Identification of Small-Molecule Inhibitors for Enterovirus A71 IRES by Structure-Based Virtual Screening

Identification of Small-Molecule Inhibitors for Enterovirus A71 IRES by Structure-Based Virtual Screening

  • J Chem Inf Model. 2025 Mar 1. doi: 10.1021/acs.jcim.4c01903.
Kaichen Wang 1,  Sean Xian Yu Lee 1,  Chaitanya K Jaladanki 2,  Wei Shen Ho 1,  Justin Jang Hann Chu 3,  Hao Fan 2 4 5,  Christina Li Lin Chai 1
Affiliations

Affiliations

  • 1 Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore, Block S4A, Level 3, 18 Science Drive 4, 117543 Singapore, Singapore.
  • 2 Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix #07-01, Singapore 138671, Singapore.
  • 3 Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, 117545 Singapore, Singapore.
  • 4 Synthetic Biology Translational Research Program and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
  • 5 Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.
PMID: 40022654 DOI: 10.1021/acs.jcim.4c01903
Abstract

Structured RNAs play a crucial role in regulating gene expression, which includes both protein synthesis and RNA processing. Dysregulation of these processes is associated with various conditions, including viral and Bacterial infections, as well as Cancer. The unique tertiary structures of structured RNAs provide an opportunity for small molecules to directly modulate such processes, making them promising targets for drug discovery. Although small-molecule inhibitors targeting RNA have shown early success, in silico strategies like structure-based virtual screening remain underutilized for RNA-targeted drug discovery. In this study, we developed a virtual screening scheme targeting the structural ensemble of EV-A71 IRES SL II, a noncoding viral RNA element essential for viral replication. We subsequently optimized the experimentally validated hit compound IRE-03 from virtual screening through an "analog-by-catalog" search. This led to the identification of a more potent IRES inhibitor, IRE-03-3, validated through biochemical and functional assays with an EC50 value of 11.96 μM against viral proliferation. Our findings demonstrate that structure-based virtual screening can be effectively applied to RNA targets, providing exciting new opportunities for future Antiviral drug discovery.

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