A computational repurposing study of antivirals targeting Lassa Virus nucleoprotein and inosine monophosphate dehydrogenase via network pharmacology, Density Function Theory (DFT), molecular docking and dynamics simulation

Lassa fever (LF) is a zoonotic viral hemorrhagic disease endemic in West Africa, particularly Nigeria, where recurrent outbreaks continue to pose significant public health challenges. The limited availability of effective antiviral therapies necessitates the identification of repurposable drugs capable of inhibiting viral replication and modulating host molecular targets involved in LF pathogenesis. This study employed an integrated computational drug-repurposing strategy targeting Lassa virus nucleoprotein (NP) and inosine monophosphate dehydrogenase (IMPDH) using network pharmacology, Density Functional Theory (DFT), molecular docking, and molecular dynamics simulations (MDs). Chemical structures of eragidomide, remdesivir, and sofosbuvir were retrieved from the PubChem database, and potential targets were predicted using SwissTargetPrediction. LF-associated genes were obtained from GeneCards, DisGeNET, OMIM, and MalaCards databases, while overlapping targets were identified using Venny 2.1.0. Protein–protein interaction networks were constructed using STRING and visualized in Cytoscape, followed by functional enrichment analysis using the ShinyGO platform. Molecular docking and visualization were performed using BIOVIA Discovery Studio, UCSF Chimera, and PyRx, while Maestro software was used for MM-GBSA binding free-energy calculations and pharmacophore modeling. Docking results demonstrated strong binding interactions with NP and IMPDH, with eragidomide showing the highest affinity toward NP (-11.3 kcal/mol) and favorable interaction with IMPDH (-9.0 kcal/mol). MD simulations conducted over 100 ns indicated stable binding within NP, IMPDH, and EGFR complexes. DFT calculations yielded a total electronic energy of -1973.853045 Eh with an RMS gradient norm of 0.000003 Eh/a₀, confirming optimized and stable molecular geometry of eragidomide. These findings suggest eragidomide as a promising multi-target antiviral candidate against LF replication and host signaling pathways.