methyl-3-methoxy-4-hydroxystyryl-ketone and Alzheimer-Disease

Acetylcholinesterase (AChE) enzyme and myeloid differentiation 2 protein (MD2) are two critical proteins involved in Alzheimer's disease (AD). Since the nature of the active site of AChE and the binding pocket of MD2 are similar, some ligands can inhibit both of them appropriately. Oxidative stress has also been known as an important cause of AD. Designing an effective common inhibitor with antioxidant activity to inhibit AChE and MD2 proteins is the main goal of this work. In this regard, we used tacrine molecule with a high ligand efficiency (LE) and dehydrozingerone (DHZ) with anti-inflammatory, antioxidant and anti-Alzheimer activities. Some modifications on DHZ structure can increase its antioxidant activity. So, tacrine molecule was combined with modified DHZ to present a new multi-target-directed ligand (MTDL). The ability of the designed ligand to inhibit AChE and MD2 proteins was confirmed by molecular docking, molecular dynamics (MD) simulation, and binding-free energy calculations. Therefore, the designed ligand can target two proteins involved in AD. It can also act as a potent antioxidant. In general, three important causative agents of AD are targeted by the designed ligand. Moreover, the inhibition of MD2, as the main source of oxidative stress, significantly reduces the production of free radicals.

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Catalytic Domain; Cholinesterase Inhibitors; GPI-Linked Proteins; Humans; Hydrogen Bonding; Ligands; Lymphocyte Antigen 96; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Oxidative Stress; Structure-Activity Relationship; Styrenes; Tacrine; Thermodynamics

Curcumin, a dietary polyphenol, has shown a potential to act on the symptoms of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, as a consequence of its antioxidant, anti-inflammatory and anti-protein aggregation properties. Unfortunately, curcumin undergoes rapid degradation at physiological pH into ferulic acid, vanillin and dehydrozingerone, making it an unlikely drug candidate. Here, we evaluated the ability of some curcumin by-products: dehydrozingerone (1), its O-methyl derivative (2), zingerone (3), and their biphenyl analogues (4-6) to interact with α-synuclein (AS), using CD and fluorescence spectroscopy. In addition, the antioxidant properties and the cytoprotective effects in rat pheochromocytoma (PC12) cells prior to intoxication with H2O2, MPP+ and MnCl2 were examined while the Congo red assay was used to evaluate the ability of these compounds to prevent aggregation of AS. We found that the biphenyl zingerone analogue (6) interacts with high affinity with AS and also displays the best antioxidant properties while the biphenyl analogues of dehydrozingerone (4) and of O-methyl-dehydrozingerone (5) are able to partially inhibit the aggregation process of AS, suggesting the potential role of a hydroxylated biphenyl scaffold in the design of AS aggregation inhibitors.

Topics: Adrenal Gland Neoplasms; alpha-Synuclein; Alzheimer Disease; Animals; Antioxidants; Cell Line, Tumor; Curcumin; Cytoprotection; Guaiacol; Parkinson Disease; Pheochromocytoma; Rats; Styrenes