Fungal Metabolites as Multi-Target Modulators of Alzheimer’s Disease: An Integrated In Silico Docking and Molecular Dynamics Approach

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options offering only symptomatic relief. Natural fungal metabolites have recently gained attention for their neuroprotective potential. In this study, an extensive library of 18,349 fungal compounds was retrieved from the NPAtlas database and systematically screened for drug-likeness, ADMET properties, and toxicity profiles. Successive filtering reduced the dataset to 99 drug-like molecules, of which five candidates—Sonomolide A, Steperoxide A, RP-1551-M2, Illudin J, and Pericoannosin F—were selected for detailed analysis. These compounds demonstrated favourable physicochemical properties, compliance with Lipinski’s Rule of Five, high gastrointestinal absorption, blood–brain barrier permeability, and acceptable toxicity margins (Class 6). Molecular docking against five AD-related targets (AChE, CBNR2, CHRM1, CHRM4, & D1B dopamine receptor) revealed strong binding affinities, with Steperoxide A showing the highest affinity for AChE (−8.0 kcaL/moL) and CBNR2 (−9.0 kcaL/moL), while RP-1551-M2 displayed consistent interactions with muscarinic and dopamine receptors. MD simulations confirmed stable protein–ligand interactions, with RMSD values ranging from 0.10–1.75 nm and hydrogen-bond counts between 47–252 throughout the trajectory. Stable radius of gyration values (2.74–3.95 nm) further indicated the maintenance of structural compactness and binding integrity, and the results also showed good stability and favourable interaction profiles. Collectively, these findings highlight fungal metabolites—particularly Steperoxide A and RP-1551-M2—as promising multi-target neuroprotective scaffolds with potential therapeutic relevance in AD.