Viruses 2025, 17(6), 814; https://doi.org/10.3390/v17060814 (registering DOI) - 4 Jun 2025
Abstract
Norovirus, a major cause of acute gastroenteritis, possesses a single-stranded positive-sense RNA genome. The viral 3C-like cysteine protease (3CLpro) plays a critical role in processing the viral polyprotein into mature non-structural proteins, a step essential for viral replication. Targeting 3CLpro
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Norovirus, a major cause of acute gastroenteritis, possesses a single-stranded positive-sense RNA genome. The viral 3C-like cysteine protease (3CLpro) plays a critical role in processing the viral polyprotein into mature non-structural proteins, a step essential for viral replication. Targeting 3CLpro has emerged as a promising strategy for developing small-molecule inhibitors against Norovirus. In this study, we employed a combination of virtual screening and the FlipGFP assay to identify potential inhibitors targeting the 3CLpro of Norovirus genotype GII.4. A library of approximately 58,800 compounds was screened using AutoDock Vina tool, yielding 20 candidate compounds based on their Max Affinity scores. These compounds were subsequently evaluated using a cell-based FlipGFP assay. Among them, eight compounds demonstrated significant inhibitory activity against 3CLpro, with Gedatolisib showing the most potent effect (IC50 = 0.06 ± 0.01 μM). Molecular docking and molecular dynamics simulations were conducted to explore the binding mechanisms and structural stability of the inhibitor–3CLpro complexes. Our findings provide valuable insights into the development of antiviral drugs targeting Norovirus 3CLpro, offering potential therapeutic strategies to combat Norovirus infections.
Full article
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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