Citation: Zhenxing Li, Yue Ding, Xinxin Tuo, Jinhong Hu, Taihong Zhang, Xiang Zhou, Liwei Liu, Song Yang. Structure-based drug repurposing targeting pathogenic virus superfamily 1 helicase: An integrated multi-computational screening and bioactivity identification strategy[J]. Chinese Chemical Letters, ;2025, 36(9): 110737. doi: 10.1016/j.cclet.2024.110737 shu

Structure-based drug repurposing targeting pathogenic virus superfamily 1 helicase: An integrated multi-computational screening and bioactivity identification strategy

State Key Laboratory of Green Pesticides, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang 550025, China

Received Date: 15 September 2024
Revised Date: 25 November 2024
Accepted Date: 6 December 2024
Available Online: 7 December 2024

Figures(3)

Structure-based virtual screening utilizing the approved drugs is an intriguing and laudable approach to excavate novel alternatives for different indications based on the vast amount of reported experimental data. Virus superfamily 1 helicase could resolve hydrogen bonds between base pairs and participate in nucleic acid replication and has emerged as a potential target for managing virus infection. Nonetheless, current drug exploitation targeting viral helicases is still in infancy. This work establishes an intelligent multi-computational screening programme to screen potential inhibitors targeting tobacco mosaic virus (TMV) helicase using Food and Drug Administration (FDA)-approved commercially available molecule library. The ranked top 6 hits were further validated by root mean square deviations/fluctuations (RMSD/F), molecular mechanics Poisson Boltzmann surface area (MM-PBSA), density functional theory (DFT) calculations, and bioactivity evaluation. Encouragingly, lumacaftor (ΔE_total = −29.0 kcal/mol, K_d = 0.22 µmol/L, half maximal inhibitory concentration (IC₅₀) = 162.5 µmol/L) displayed superior binding strength and enzyme inhibition against TMV helicase compared to ningnanmycin (K_d = 9.35 µmol/L, IC₅₀ > 200 µmol/L). Therefore, lumacaftor may be able to inhibit TMV replication by binding to helicase and interfering with its biofunctionability. Besides, the lumacaftor-helicase binding mode changes from H-bonding/electrostatic interactions to hydrophobic interactions in trajectory analysis. Overall, current findings suggest this state-of-the-art stratagem is fruitful and has the potential to be engaged in rapid mining of other target inhibitors for disease treatment.
- Intelligent screening,
- Drug repurposing,
- Helicase,
- Virus inhibitor,
- Bioassays
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沈阳化工大学材料科学与工程学院沈阳 110142