Discovery of sugar-based natural framework as phytopathogenic virus capsid protein inhibitors using a...

The prompt and efficient identification of targeted inhibitors against unscrupulous pathogenic viruses holds promise for preventing epidemic disease outbreaks. Herein, a comprehensive multichannel screening method (multiple docking cross-validation, molecular dynamics simulation, and density functional theory calculation) integrated with bioactivity identification is rationally established using sugar-based natural ligand libraries to target tobacco mosaic virus (TMV) capsid proteins. Encouragingly, compounds A0 (K_d = 0.14 μM) and A4 (K_d = 1.43 μM) were evaluated to have excellent binding capacities to TMV capsid protein, evidently exceeding that of viricide Ningnanmycin (K_d = 3.47 μM) by 24.8 and 2.4-folds. Moreover, A0 and A4 significantly down-regulated the expression of capsid proteins at the transcriptional level, effectively blocking the biosynthesis and assembly of TMV in tobacco. Additionally, bioactivity evaluation illustrated that the anti-TMV curative effects of A0 (EC₅₀ = 310.9 μg/mL) and A4 (EC₅₀ = 371.2 μg/mL) were comparable to Ningnanmycin (EC₅₀ = 343.8 μg/mL). Considering the availability, cost and synthesis difficulty of precursors, the more affordable A4 is reckoned to be a promising candidate for capsid protein inhibitors and warrants further exploration in follow-up studies. Current findings highlight that this state-of-the-art virtual strategy, integrated with bioactivity validation, facilitates the discovery of targeted candidates to combat pathogenic viruses.