Azadirachta indica Natural Active Ingredients to Cure Mpox: In silico Targeting VP39

Abstract

VP39 is an essential enzyme in the Mpox virus acting as methyltransferase for RNA capping to translate viral mRNA during human infection. This enzyme adds a 7-methylguanosine cap at the 5' end of viral mRNAs, imitating the capping mechanism of the host cells to evade immune detection. Efficient RNA capping carried out by VP39 enhances protein expression and viral replication, thereby contributing to the pathogenesis of the virus. Thus, the agent VP39 is highly attractive as a therapeutic target for inhibiting Mpox virus replication. In silico work were performed on the 2'-O-methyltransferase activity in VP39 and explored for inhibition by natural compounds from Azadirachta indica (neem). Stigmasterol, which is the most active of the phytochemicals in the neem, is a phytosterol exhibiting anti-inflammatory, antioxidant, and immune-modulatory properties. Molecular docking studies using Autodock Blow on the SeamDock web-based platform indicate a binding affinity of -7.98 kcal/mol of stigmasterol with the enzyme VP39. This negative figure indicates strong interactions and can be interpreted to put stigmasterol in contention as an antagonist for VP39-mediated RNA capping. This would disrupt viral replication. For this reason, understanding compound-protein interactions is essential in paving a better path toward neem-based therapies. Such linkages of the inhibitory action of stigmasterol and other neem compounds to the activity of VP39 would form part of their therapeutic relevance. Linking findings of molecular docking with drug discovery clearly show the need to find compounds with strong binding affinities to prime viral targets. However, many hurdles need to be crossed before all this interesting progress can be translated into a fairly clinical setting, including verifying efficacy and safety at the level of pharmacokinetics, standardizing different compounds, and obtaining regulatory approvals by means of robust clinical trial programs. All of these phases are necessary for pre-discovery in therapeutic applications against the Mpox virus.