<i>In silico</i> identification of Nipah virus protein inhibitors from secondary metabolites of medicinal plants using a high-throughput virtual screening approach

The Nipah virus (NiV), a highly pathogenic zoonotic virus of the <i>Paramyxoviridae</i> family, poses significant threats with its alarming mortality rates and pandemic potential. Despite historical cases, effective therapeutics remain elusive, prompting urgent exploration of potential antivirals. In this study, a structure-based virtual screening approach was employed to evaluate 690 metabolites sourced from ten medicinal plants (<i>Allium sativum, Andrographis paniculata, Cocos nucifera, Euphorbia hirta, Euphorbia neriifolia, Moringa oreifera, Ocimum basilicum, Piper nigrum, Vitex negundo, and Zingiber officinale</i>) for their antiviral activity against Nipah virus proteins. Through targeted and blind docking experiments, forty-three (43) compounds were found to exhibit high binding affinities (≤ -8 Kcal mol^-1) and validated site-specificity. Subsequent analysis of the ADMET properties of these compounds, along with off-target docking to swine receptors, six (6) compounds with profiles akin to approved drugs and minimal off-target binding were identified. Stability screening <i>via</i> 100 ns and 300 ns molecular dynamics simulations identified two (2) of the six compounds that demonstrated sustained dynamic stability over an extended duration, coupled with favorable binding energies from MM-(GB/PB)SA calculations and biologically significant binding modes and residue interactions. Betulinic acid and CID 118716357 exhibited significant potential as inhibitors of Nipah virus fusion (F) glycoprotein trimer by targeting the oligomerization sites used to form the functional hexamer-of-trimer assembly. Coupled with their dynamic stability and favorable ADMET profiles in both human and swine conditions, these findings make them good candidates for subsequent <i>in vitro</i> testing and further biological screening in the quest for potent antiviral drugs targeting Nipah virus proteins.