Selenoergothionein as a Potential Inhibitor against Amyloid β-Protein (Aβ): Docking and Molecular Dynamics Studies

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, encircling the deterioration of cognitive functions and behavioral changes, characterized by the aggregation of amyloid β-protein (Aβ) into fibrillar amyloid plaques in elected areas of the brain with the lipid-carrier protein apolipoprotein E (apoE), the microtubule associated protein tau, and the presynaptic protein α-synuclein. High levels of fibrillary Aβ, the main constituent of senile plaques, are deposited in the AD brain that outcome in the thrashing of synapses, neurons and destruction of neuronal role. Aβ is derived from the amyloid precursor protein through sequential protein cleavage by aspartyl protease, β-secretase and presenilin-dependent β-secretase triggering a spill of events such as oxidative damage, neurotoxicity, and inflammation that contributes to the progression of AD. Therefore the Aβ protein may be a target for anti-Alzheimer drugs. Aβ protein was retrieved from the Protein Data Bank and energy minimized and subjected to molecular dynamic simulations using NAMD 2.9 software with CHARMM27 force field in water. The Aβ protein structure was energy minimized by 25,000 steps for 500 ps and pretend 100,000 steps for 2ns. The ergothionein and selenoergothionein, which were found to exhibit amyloid inhibitory effect, were selected and the 3D structure files of those compounds were retrieved from Zinc database. The two compounds were then docked into the active site of Aβ protein with AutoDock Vina in PyRx Virtual Screening tool. The two compounds were showed best binding energies of-9.8, and-7.9 kcal/mol correspondingly. The binding interactions of compounds with active site of Aβ protein model suggested that the amino acid residues (SER8, GLN15, and LYS16) play a key role for drug design. The predicted pharmalogical properties of two compounds, among them selenoergothionein is well within the range of a drug molecule with good ADME profile. Therefore, would be interesting towards progress of persuasive inhibitor against Aβ protein.