Discovery of sugar-based natural framework as phytopathogenic virus capsid protein inhibitors using a state-of-the-art multiple screening strategy

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.