The Study Of Structure-based Virtual Screening With Acetylcholinesterase As Targets

Alzheimer’s disease is a serious threat to the health and disease in the elderly people, Which lead to the progressive degeneration of the central nervous system to affect the function of cognition, memory, language, visual space, So is also known as Senile Dementia. However, the pathogenesis of alzheimer’s disease is not very clear, Which needs to be further detailed research. one of the main reasons is Choline deficiency,So the drugs which an increase choline effect has played an important role in the treatment of alzheimer’s disease. The main drugs for the treatment of AD at present are Tacrine (Tacrine), Rivastigmine, huperzine A, Donepezil, etc. They are all with acetyl cholinesterase (AChE) having inhibitory effect on enzyme activity to reach a certain therapeutic effect. However, The clinical effect of the existing commercial AChE inhibitors is limited, And they have been accompanied by varying degrees of side effects in the process of treatment. So hunting for new type of highly active AChE inhibitors is very be necessary.A list of hybrids of Tacrine and melatonin showed high activities on the human acetylcholine esterase, their IC50values range from sub-nanomolar to picomolar, Significantly higher than the previously reported series of inhibitor molecules. In this article, we based on the series of highly reactive compounds by molecular docking, binding free energy calculation(MM/PBSA) to get a very good linear correlation in combination with the calculated value of free energy and biological activity test values,which determines the validity of the molecular docking model. By combining the free energy decomposition, The important amino acid residues in the cavity can be found with human acetyl cholinesterase (h-AChE).We get a pharmacophore model based on SBP (Structure-based Pharmacophore), keep important pharmacophore element features in the pharmacophore features refer to the determined important amino acid residues in the cavity, and then verify the rationality of the pharmacophore by using the test molecular library which consists of highly reactive molecules and unknown active moleculars. Highly reactive molecules can be well filtered from the library to verify the effectiveness of the pharmacophore model. Using the pharmacophore for virtual screening to the molecular library which built by ourselves, to get the compounds contains tacrine ring, amide linkage of methylene long chain molecules and coumarin ring. we get the reasonable combination of model between inhibitors and receptor via molecular docking,then find that they all are living better enzyme activity on the molecular biological activity test,One of the most optimal molecular its enzyme activity in vitro is doubled compared with classical inhibitor tacrine,for the future optimization of inhibitor molecules provides an important guiding significance...