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Infections caused by the monkeypox virus (MPXV) have continued to be transmitted significantly in recent years. However, understanding the transmission mechanism, risk factors, and consequences of infection are still limited. Structure-based drug design for MPXV is at an early stage due to the availability of protein structures that have been determined experimentally. However, the structure of the A42R profilin-like protein of MPXV has been solved and submitted to the structure database. This study illustrated an in silico structure-based approach to identify the potential hit compound against A42R of MPXV. Here, 65 Plantago lanceolata compounds were computationally screened against A42R of MPXV. Virtual screening identified top five hits (i) Luteolin 7,3′-Diglucuronide (PubChem ID: 44258091), (ii) Luteolin 7-Glucuronide-3′-Glucoside (PubChem ID: 44258090), (iii) Plantagoside (PubChem ID: 174157), (iv) Narcissoside (PubChem ID: 5481663), and (v) (AlphaE,8S,9R)-N-(3,4-Dihydroxyphenethyl)-8-[(3,4-Dihydroxyphenethyl)Carbamoyl]-9-(1,3-Benzodioxole-5-Yl)-3aalpha,7aalpha-Ethano-1,3-Benzodioxole-5-Acrylamide (PubChem ID: 101131595), with binding energy <−9.0 kcal/mol that was further validated by re-docking and molecular dynamic (MD) simulation. Interaction analysis of re-docked poses confirmed the binding of these top hits to the A42R protein as reported in the reference compound, including active residues ARG114, ARG115, and ARG119. Further, MD simulation and post-simulation analysis support Plantagoside and Narcissoside for substantial stability in the binding pocket of viral protein contributed by hydrogen and hydrophobic interactions. The compounds can be considered for further optimisation and in vitro experimental validation for anti-monkeypox drug development. Full article