Structure-based drug designing for potential antiviral activity of selected natural product against Monkeypox (Mpox) virus and its host targets.

Monkeypox virus (MPV/MPXV/hMPXV) is a zoonotic infection that is a causative agent of monkeypox disease, which is mainly endemic in West and Central Africa regions, but recent trends suggested that the virus is transmitted around 116 countries worldwide and is still spreading in multiple non-endemic countries, causing global outbreaks. The current therapeutic options for Mpox are limited, with the WHO temporarily recommending smallpox drugs. This suggests an urgent need to discover new therapeutics that may target both viral and host markers involved in the virus life cycle. Curcumin, a polyphenolic natural compound, has broad-spectrum pharmacological activity in both DNA and RNA viruses. Therefore, this study was planned to evaluate the antiviral properties of curcumin against MPXV proteins as well as induced host targets using computational approaches, such as gene target identification, PPI network analysis, antiviral activity prediction, and molecular docking. Our network pharmacology and docking results demonstrated that curcumin majorly targets Mpox DNA polymerase holoenzyme, Methyltransferase VP39, A42R profilin-like protein, envelope protein E8, and TNF, MAPK, NFKB1, and PTGS2 to regulate host inflammatory pathways such as TNF, NF-κB, and MAPK signaling during Mpox infection. Further, we found that curcumin has a strong binding affinity toward the DNA polymerase of MPXV compared to Cidofovir, an approved inhibitor of DNA polymerase. Collectively, our findings suggested that curcumin may have potential use as a multi-targeted antiviral agent against emerging Mpox, encouraging future research that provides the molecular basis for exploring the role of curcumin as a broad-spectrum antiviral agent during viral outbreaks.

Graphical abstract: The ligand binding site of MPXV DNA polymerase shows the molecular interactions with curcumin and amino acids present on the active site of the protein.