Drug Repurposing Approaches for Lassa Virus from Secondary Metabolites of Medicinal Fungi: An Insight from Multifaceted Drug Designing Approaches

Lassa fever is a viral hemorrhagic fever caused primarily by the Lassa virus (LASV). There is no specific drug for treating Lassa fever, highlighting the need for a new therapeutic drug. In this study, 350 fungal metabolites were retrieved from the Medicinal Fungi Secondary Metabolite and Therapeutics (MeFSAT) database for docking with the nucleoprotein of the Lassa virus. We used the Schrödinger suite for molecular docking, molecular dynamic simulations, free binding energy parameters, HOMO and LUMO, and toxicity profiles to identify suitable drug candidates for the Lassa virus from medicinal fungi. The molecular docking study revealed that phelligridin-I, Formula: see text-L-glutaminyl-4-hydroxybenzene, Phellibaumin A and Phelliusin A showed good binding affinities with docking scores of −10.75, −10.32, −7.66 and −7.44 kcal/mol, respectively. Consequently, molecular dynamics simulations were performed to assess the stability of these molecules with the nucleoprotein of LASV for 100 ns. In the MD simulations, phelligridin-I, Formula: see text-L-glutaminyl-4-hydroxybenzene and Phellibaumin A demonstrated good stability, with an RMSD range of less than 2.8 Å. During the stimulation period, each of these molecules had an average of 10–15 interactions with the target, indicating strong binding affinities. The MM-GBSA investigation showed that the Formula: see text binding values of the lead compounds in pre-MD were −40.59, −42.54, −73.64 and −61.63 kcal/mol. Notably, we observed that the Formula: see text binding values of these compounds in the post-MD simulation were −61.83, −59.9, −85.62 and −86.97 kcal/mol, signifying enhanced binding affinities with the nucleoprotein of LASV under thermal and pressure conditions. Examination of organ toxicity revealed that phelligridin-I, phellibumin A, and ribavirin had respiratory toxicity with probability rates of 0.82, 0.81 and 0.72, respectively. Furthermore, the toxicity endpoints revealed that ribavirin has the potential to cause two-organ toxicity, mutagenicity and BBB-barrier, with probability rates of 0.85 and 0.98, respectively, which were greater than those of fungal metabolites. This is the first report of these fungal metabolites as therapeutically active candidates for combating the Lassa virus. However, further in vitro and in vivo studies are required to determine the exact mechanism of action of these compounds against Lassa virus.