Computational mechanistic insight of fungal metabolites for novel acetylcholinesterase inhibitors

Activity of acetylcholinesterase (AChE) enzyme elevation has been frequently observed in Alzheimer’s disease (AD) and plays a key role in disease progression. Therefore, its inhibition is considered a crucial therapeutic step in the management of cognitive defects associated with AD. In this study, we screened a library of fungal metabolites using molecular docking, molecular dynamics, and PCA to identify metabolic compounds that effectively worked against AChE. An extensive database of 19,667 fungal metabolites was methodically filtered to identify compounds with drug-like properties that are suitable for neurological disorders. Of all metabolites, only four compounds inhibited AChE better than donepezil. Mangrovamide F was the most effective against AChE, followed by Libertellenone M, Tricholopardin A, and Aspeterreurone A (ΔG: −12.6 ± 0.2, −12.3 ± 0.2, −12.2 ± 0.2, −11.8 ± 0.1 kcal/mol, respectively). Aspeterreurone A had the highest LD₅₀ dose (39,800 mg/kg), followed by Tricholopardin A (8350 mg/kg), Mangrovamide F (707 mg/kg), and Libertellenone M (190 mg/kg). Over the course of the 200-ns simulation, the protein in the AChE-fungal metabolite complexes stabilized and fluctuated within the permissible range. The most important residue, TRP86, in the AChE protein often interacts with all the best-hit ligands primarily through hydrophobic interactions, for the longest period with Libertellenone M, followed by Tricholopardin A, Mangrovamide F, Donepezil, and Aspeterreurone A. According to our PCA data, Mangrovamide F (44.61%) had the highest eigenvalue rank, followed by Libertellenone M (27.49%), Aspeterreurone A (23%), and Tricholopardin A (20.02%). Mangrovamide F and Tricholopardin A were found to be the best inhibitors of AChE enzyme with acceptable LD₅₀ and have less toxicity. Further in vitro and in vivo works regarding the therapeutic effects of these fungal compounds could elaborate our findings.