¹Universiti Malaya, Institute of Ocean and Earth Sciences (IOES), Kuala Lumpur, Malaysia, ²Universiti Malaya, National Antarctic Research Centre (NARC) Malaysia, Kuala Lumpur, Malaysia, ³Institute of Nature Conservation, Polish Academy of Sciences, Mickiewicza, Poland, ⁴Universiti Malaya, Institute of Biological Sciences, Kuala Lumpur, Malaysia

Background: Neurotoxicity is a central contributor to the onset and progression of neurodegenerative disorders, making effective therapeutic strategies difficult to achieve. Extremophilic fungi, such as the Arctic species Pseudogymnoascus australis (P. australis), are known to produce diverse bioactive metabolites that may hold neuroprotective potential. Understanding these metabolites through computational multi-omics approaches may reveal novel candidates for CNS drug development.

Aims & Objectives: This study aims to investigate the neuroprotective potential of secondary metabolites derived from the Arctic fungus P. australis using an integrated in silico multi-omics approach, with a focus on identifying compounds capable of mitigating neurotoxicity.

Method: A total of 120 secondary metabolites from P. australis were screened for blood–brain barrier permeability and pharmacokinetic suitability using ADMETlab. Nine metabolites, 11-amino-undecanoic acid, 2-amino-hexadecanoic acid, KAPA, phthalic anhydride, Halaminol A, stearamide, hexadecyl isocyanate, palmitic amide, and N,N’-dicarbamimidoyltetradecanediamide were prioritized based on drug-likeness (DL > 0.83) and plasma protein binding profiles. Network pharmacology was employed to identify shared gene targets associated with neurotoxicity, followed by protein–protein interaction (PPI) network analysis to identify hub genes. GO and KEGG enrichment analyses were conducted to elucidate functional pathways. Molecular docking evaluated ligand–receptor binding affinities, and 100 ns molecular dynamics simulations assessed stability and thermodynamic feasibility of the top complexes.

Results: The nine prioritized metabolites demonstrated strong CNS-relevant pharmacokinetic properties and drug-likeness, indicating their suitability as neuroprotective candidates. Network pharmacology revealed 226 shared targets between the metabolites and neurotoxicity-associated genes. PPI analysis identified nine hub genes namely GRIA1, GRIA2, GRIA4, GRIK1, GRIK2, GRIN1, GRIN2A, GRIN2B, and GRIN2C, all of which play essential roles in excitatory neurotransmission and synaptic regulation. GO and KEGG pathway enrichment consistently highlighted the neuroactive ligand - receptor interaction pathway as a key mechanism.Molecular docking results showed strong ligand binding to synaptic receptor targets, and molecular dynamics confirmed stable interactions over 100 ns, supporting the potential functional relevance of these metabolite–protein complexes.

Discussion & Conclusions: This study presents strong computational evidence that P. australis produces bioactive metabolites capable of modulating neurotoxicity through multi-target regulation of synaptic signaling pathways. These findings establish a molecular foundation for future in vitro and in vivo investigations and highlight Arctic fungal metabolites as promising leads for central nervous system drug discovery.