Discovery of drug lead compounds for Anti-Alzheimer's disease on the basis of synaptic plasticity

Alzheimer's disease (AD) is a progressive neurodegenerative disease commonly seen in the middle-aged and the elder. Its clinical presentations are mainly memory impairment and cognitive impairment. Its cardinal pathological features are the deposition of extracellular Amyloid-β (Aβ), intracellular neurofibrillary tangles and synaptic dysfunction. The etiology of AD is complex and the pathogenesis remains unclear. Having AD would lead to awful living experience of it's patients, which may be a burden to the patient even to the public health care system. However, there are no certain cure for AD. Thus it's significant for both medical value and social meaning to find the way to cure or prevent AD and to research on the pathogenesis of AD. In this work, the molecular docking technology, pharmacokinetic analysis and pharmacological experiments were employed to analyse the natural active compounds and the mechanisms against AD based on the synaptic plasticity. A total of seven target proteins related to the synaptic plasticity and 44 natural active compounds with potential to enhance the synaptic plasticity were obtained through a literature review and network pharmacological analysis. Computer-Aided Drug Design (CADD) method was used to dock the anti-AD key target proteins with the 44 compounds. The compounds with good binding effect were screened. Three anti-AD active compounds based on the synaptic plasticity were obtained, including Curcumin, Withaferin A and Withanolide A. In addition, pharmacological experiments were carried out on Withaferin A and Withanolide A based on its good docking results. The experimental results showed that Withaferin A has good anti-AD potential and great potential to enhance synaptic plasticity. The anti-AD effect can be achieved through a multi-target synergistic mechanism.