BACE1 Inhibitor, Neuroprotective, and Neuritogenic Activities of Melatonin Derivatives

Abstract

Alzheimer’s disease (AD) is a common chronic neurodegenerative disorders. Melatonin (MLT) has been reported to be neuroprotective agent, and its modified structures exhibit potent antioxidant and anti-inflammation activities. Therefore, the activity of MLT and its derivatives against AD was investigated. Herein, the targeted enzymes, such as β-secretase (BACE1) and acetylcholinesterase (AChE), as well as the neuroprotective and neuritogenic effects on P19-derived neurons were evaluated. All the derivatives (1–5), including MLT, displayed potent inhibitory activity for BACE1, with inhibition values of more than 75% at 5 µM. A molecular docking study predicted that MLT, 5-MT, and 5 bound with BACE1 at catalytic amino acids Asp32 and the flap region, whereas 1–4 interacted with allosteric residue Thr232 and the flap region. The additional π-π interactions between 2, 3, and 5 with Tyr71 promoted ligand-enzyme binding. In addition, MLT, 1, 3, and 5 significantly protected neuron cells from oxidative stress by increasing the cell viability to 97.95, 74.29, 70.80, and 69.50% at 1 nM, respectively. Moreover, these derivatives significantly induced neurite outgrowth by increasing the neurite length and number. The derivatives 1, 3, and 5 should be thoroughly studied as potential AD treatment and neuroprotective agents.

Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer’s Disease Therapy

“…Its binding energy to other binding regions within the enzyme ranges from −6.12 to 7.10 kcal/mol with favorable fitness scores ( Figure 6 ). The interaction of Thr232 and flap region residues buttress previous molecular docking prediction of compound 1 binding pose [ 37 ]. To give a clearer picture of the stability of compound 1 interaction to BACE1 at the different binding subsites, we simulate each complex ( Figure 6 ) using the amber force field.…”

“…Besides, Pietro et al’s (2017) study of conformational ensemble and binding mode analysis of some multisite inhibitors using MD and docking method [ 36 ], studies that explore multisite targeting of BACE1 towards drug design for AD are still scarce. In this study, we selected compounds ( Figure 4 ) proposed by different authors [ 28 , 29 , 30 , 31 , 37 , 38 , 39 , 40 , 41 ] as potent BACE1 allosteric inhibitors for some computational experiments. Docking analysis revealed that these compounds bind at allosteric sites but are highly stable at the active site.…”

Novel Multifunctional Ascorbic Triazole Derivatives for Amyloidogenic Pathway Inhibition, Anti-Inflammation, and Neuroprotection

“…The P19 embryonal carcinoma cell is a pluripotent stem cell line that can be differentiated into cholinergic neurons by all transretinoic acids [ 27 , 28 , 29 ]. The P19-derived neurons exhibit many characteristics of mature CNS neurons, containing neurotransmitter acetylcholine [ 28 ], which can be used as a model to evaluate neurotoxicity and neuroprotective activity [ 29 , 30 , 31 , 32 , 33 ]. In the present study, neurotoxicity assays were performed prior to neuroprotective activity assays, with test compounds at various concentrations of 1 to 10 4 nM to evaluate nontoxic concentrations.…”

Anti-Inflammatory Comparison of Melatonin and Its Bromobenzoylamide Derivatives in Lipopolysaccharide (LPS)-Induced RAW 264.7 Cells and Croton Oil-Induced Mice Ear Edema

“…Interestingly, an in silico study predicted that the N1 -position lipophilic-substituted melatonin derivative ( N -(2-(1-4-bromobenzoyl-5-methoxy-1H-indol-3-yl)ethyl) acetamide, BBM) could not be metabolized by CYP1A2, which prolonged its half-life compared with melatonin [ 22 ]. In contrast, while another melatonin derivative with a 4-bromobenzoyl amide substitution at the N -acyl side chain (4-bromo- N -(2-(5-methoxy-1H-indol-3-yl)ethyl)benzamide, EBM) was predicted to be a substrate of CYP1A2, it displayed a potent antioxidant and neuroprotective effect [ 20 , 23 ]. Fan et al [ 24 ] also reported that N -salicyloyl tryptamine derivatives are potential anti-neuroinflammation agents that act by decreasing the production of proinflammatory mediators, NO, PGE 2 and TNF-α.…”