Computational screening of foxtail millet (Setaria italica (L.) P.Beauv.) polyphenols for finding β-secretase (BACE 1) inhibitors that target the amyloidogenic pathway in Alzheimer's disease

Abstract

Abstract BACKGROUND: Foxtail millet (FM; Setaria italica (L.) P.Beauv.) is known for its antioxidant and neuroprotective action against Alzheimer's disease (AD); hence the present study aims to screen its polyphenols to find less toxic and potentially effective anti-Alzheimer's drugs. MATERIALS AND METHODS: The details about phyto-compounds of FM and the β-secretase enzyme (BACE 1) of AD have been retrieved from the PubChem compound database and protein data bank, respectively. The Patch Dock server was used to carry out docking experiments. Initially, all the FM phytocompounds and reference drug (MK-8931) were subjected to docking, and subsequently, the best-docked complexes were selected based on their binding energy (in kcal/mol). Rule of five and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) of selected compounds were analyzed using various computational tools. The final docking complexes were developed by using PyMOL. RESULTS: The molecular docking results revealed that among the 24 polyphenols studied, two compounds, namely N′-p-coumaroyl-N″-caffeoylspermidine (NPCNCS) and di-P-coumaroylspermidine (DPCS), demonstrated strong binding to the active site of β-secretase. and exhibited higher binding energies of -300.75 kcal/mol and -193.41 kcal/mol, respectively, in comparison to the reference drug MK-8931, with a binding energy of -154.36 kcal/mol. These compounds established hydrogen bond interactions with catalytic dyad (Asp 32 and Asp 228) and other accessory interactions with residues of the “flap” hairpin loop and “10s loop” of the β-secretase active site involved in the stabilization of substrate/inhibitor binding. In a nutshell, the NPCNCS and DPCS have shown more robust binding affinity than MK-8931 and docked well into the interior side of the active site. On the other hand, NPCNCS and DPCS have satisfied the RO5 and ADMET filters. CONCLUSIONS: The in silico analysis of FM polyphenols revealed that the N′-p-coumaroyl-N″-feruloylspermidine and di-P-coumaroylspermidine compounds exhibited non-toxic, permeability to blood-brain barrier and solid binding affinity toward β-secretase enzyme thereby; these millet compounds might be considered as β-secretase inhibitors for treating AD.