Molecular Dynamics Study and Prediction of Oral Toxicity of Calebin A in Alzheimer’s Disease

Alzheimer’s Disease (AD) is characterized by neurodegenerative changes that lead to the emergence of symptoms such as memory loss, difficulties in speaking, performing daily tasks, among others. The pathophysiology of AD is complex, but in general, its onset is related to the formation of neurofibrillary tangles and senile plaques; and some studies also report a link with neuroinflammatory processes and oxidative stress. Acetylcholinesterase (AChE) is an important pharmacological target due to its role in the pathophysiology of AD, as is the enzyme nitric oxide synthase (iNOS), which also contributes to the development and progression of the disease. The treatments available for AD only aim to delay the symptoms and improve quality of life, as there is no cure. In this context, because they contain substances that act synergistically against multiple molecular targets, overcoming various disadvantages, natural products are shown to be good alternatives for use in the planning of drugs for the treatment of neurodegenerative diseases. In addition, the use of computational methods is an important approach to overcoming the limitations imposed by traditional experimental methods. In view of this, this study aimed to use molecular dynamics simulations and in silico lethal dose assessment to help better understand the conformational behavior of the natural product calebin A and identify potential toxicological risks. GROMACS (GROningen MAchine for Chemical Simulation) software version 2020 and ProTox 3.0 were used for this purpose. The results of the interactions between Calebin A and AChE showed that the values are within the acceptable range 1–3 Å, without major disturbances. In the simulation between the compound and iNOS, it is possible to note that the complex remained stable during its time in the active site. The predicted LD₅₀ value is considered to be slightly toxic and is considered safe at low doses. It is hoped that these results will contribute to the planning of drugs for the treatment of Alzheimer’s disease.