ABSTRACT
Coumarins belong to the family of benzopyrone and have a variety of biological activities, including the management of Alzheimer’s disease (AD). Inhibition of beta-secretase-I (BACE1), acetylcholinesterase (ACHE), and phosphodiesterase-4D (PDE4D) is important for the management of AD progression. The present study is framed to identify coumarin analogous as potent antagonists of ACHE, BACE1, and PDE4D by stringent in silico checkpoints. A list of coumarin derivatives was collated from the ChEBI database. The pkCSM database was used to predict the ability of compounds to cross the blood–brain barrier. Molecular docking of prioritized compounds was screened against BACE1, ACHE, and PDE4D protein targets using AutoDock vina via using POAP pipeline. Lead hit compounds molecular dynamics for 150 ns were performed by GROMACS. Binding free energy, per residue energy contribution, and principal component analysis of the complexes were performed for MD trajectories. Finally, gene set pathway enrichment and network analysis of BACE1, ACHE, and PDE4D inhibitors were performed by the KEGG database and Cytoscape software, respectively. Out of 379 coumarins shortlisted, 69 were found to act on the central nervous system. The study provided 3 important coumarin derivatives (decursin, farnesiferol A, and 2-Acetamido-6H-dibenzo[b,d]pyran-6-one) as potent lead molecules against BACE1, ACHE, and PDE4D) for the management of \ AD. Along with these 3 molecules, 11, 21, and 16 compounds were predicted to inhibit BACE1, ACHE, and PDE4D, respectively. Additionally, these compounds found to regulate neuroactive ligand-receptor interaction; GABAergic synapse; serotonergic synapse; phenylalanine, tyrosine, glycine, serine, and threonine metabolism; cGMP-PKG, calcium signalling pathway, etc. that are directly linked to AD pathogenesis. The resulting list of coumarins represented in this study needs wet lab research for novel candidate development against AD.
