Structure-Based Discovery of Novel Zika Virus NS5 Methyltransferase Inhibitors through Large-Scale Virtual Screening and Comparative Benchmarking

Lu Li

Co-Presenters: Individual Presentation

College: Hennings College of Science Mathematics and Technology

Major: BS.BIO/CELL/MOLEC

Faculty Research Mentor: Kar, Supratik  

Abstract:

Zika virus continues to pose a serious public health risk due to its association with congenital Zika syndrome and neurological complications, and no approved antiviral therapies currently exist. The methyltransferase (MTase) domain of the NS5 protein plays an essential role in RNA capping, maintaining genome stability, and facilitating immune evasion, making it a biologically validated and druggable target for therapeutic development. The primary goal of this study was to identify novel small molecule inhibitors of Zika virus methyltransferase that demonstrate stronger predicted binding performance than previously reported reference compounds and expand the available chemical space for antiviral discovery. Using the high-resolution crystal structure 5WXB obtained from the Protein Data Bank, we evaluated multiple complementary ligand sets. A curated group of eleven inhibitors reported in the literature was compiled as benchmarking controls, and 614 structurally similar analogues were retrieved from the Mcule using similarity-based searching. In parallel, a large-scale screening effort was conducted using more than 50000 compounds from the ChemDiv Small Molecule Inhibitor database to explore broader chemical diversity. Comparative ranking against the control ligands enabled objective evaluation of candidate performance. After systematic screening and analysis, two lead compounds emerged as top candidates, one originating from the Mcule similarity derived dataset and one from the ChemDiv library. Both compounds exhibited superior predicted binding affinity and improved ligand efficiency relative to all reference inhibitors. These results highlight two promising chemical scaffolds with enhanced predicted interactions within the validated active site and provide strong candidates for subsequent biochemical assays and antiviral evaluation.