<i>In Silico </i>Screening of Phenylpropanoid and Polyketide Phytochemicals as Potential Inhibitors of Mpox Viral Proteins

Mpox, a viral zoonotic disease similar to smallpox, poses significant public health challenges, particularly in Africa, with recent outbreaks in regions like India emphasising its global threat. In this study, we propose a novel strategy to combat the mpox virus infection by targeting surface proteins critical for viral entry and fusion. Using advanced computational techniques, we predicted and refined the 3D structures of six MPXV surface proteins: Q8V4U9 (A30L), Q8V4V7 (A21L), Q8V4Y0 (E8L), Q8V4Z8 (M5R), Q8V503 (G10R), and Q8V509 (G2L). A total of 18,877 phytochemicals from the phenylpropanoids and polyketides superclasses and 3,575 antiviral therapeutics were retrieved from the IMPPAT database. After removing overlapping compounds, 888 phytochemicals were subjected to SWISS ADME screening, resulting in 191 lead-like and drug-like molecules. These compounds were docked against MPXV surface proteins using PyRx, and their top-scoring 2D and 3D interactions were visualised using Discovery Studio. The key docking results were as follows: Q8V4U9: -7.6 kcal/mol with Pongaglabrone, Boeravinone E, and Boeravinone F, each forming one hydrogen bond at SER118, SER46, and ASN37, respectively. Q8V4V7: -8.2 kcal/mol with 2H-1-Benzopyran-2-one, forming a hydrogen bond at ALA62. Q8V4Y0: -8.9 kcal/mol with Pongaglabrone and Liquiritigenin, forming hydrogen bonds at ASN92, ASN79, and SER6. Q8V503: -8.8 kcal/mol with Skullcapflavone I, forming a hydrogen bond at GLN147. Q8V509: -8.5 kcal/mol with Pongaglabrone, forming a hydrogen bond at SER110. Q8V4Z8: -8.8 kcal/mol with Skullcapflavone I, forming hydrogen bonds at LEU73 and ALA71. Our results suggest that Pongaglabrone and Skullcapflavone I are promising therapeutic candidates against MPXV. In conclusion, this study highlights Pongaglabrone and Skullcapflavone I as potent phytochemical candidates targeting key MPXV surface proteins, offering a promising, nature-derived approach for developing effective antiviral therapies against mpox.