DFT-Based Elucidation and Evaluation of Selenium-Modified Tacrine Derivatives: Theoretical and Physicochemical Insights for Alzheimer’s Disease Therapy

The incorporation of selenium into tacrine derivatives has been explored as a novel strategy to enhance therapeutic efficacy while minimizing toxicity in the treatment of neurodegenerative diseases such as Alzheimer's. This study utilized computational and experimental approaches, including Density Functional Theory (DFT), molecular docking, pharmacokinetic profiling, and toxicological predictions, to evaluate the potential of these derivatives. The selenium-modified compounds demonstrated improved electronic properties, such as narrower HOMO-LUMO gaps and optimized electronegativity, resulting in enhanced stability and reactivity. Pharmacokinetic analyses revealed favorable absorption, distribution, and blood-brain barrier penetration, while toxicological assessments indicated reduced hepatotoxicity and skin sensitization risks compared to tacrine. Molecular docking and dynamic simulations highlighted strong and stable interactions of the derivatives with critical enzymes, including acetylcholinesterase (AChE) and beta-secretases (BACE1 and BACE2). Compounds <b>12</b> and <b>13</b>, in particular, emerged as the most promising candidates due to their superior stability and binding affinity. These findings underscore the potential of selenium-modified tacrine derivatives as safer and more effective therapeutic agents for Alzheimer's disease, warranting further experimental validation.