The Molecular Mechanism Study Of Selectivity Of TZ2PA6As Acetylcholinesterase Inhibitors In Different Species

Acetylcholinesterase (AChE) is an enzyme with a very high catalytic activity that degraded the neurotransmitter acetylcholine, and producing choline and an acetatet group. AChE widely exists in neuromuscular junctions, cholinergic nervous system and the red blood cell membranes. It is the target of many Alzheimer’s Dementia drugs, nerve gases and insecticides. The acetylcholinesterase inhibitors can increase the level of the choline in the pest, and poison them. The representative pesticides are organophosphorus and carbamate derivates, however, this kind of pesticide are harmful for the environment and human beings. In recenet years, it appears lots of new acetylcholinesterase inhibitors, and most of which aer reversible. The inhibitors interact with acetylcholinesterase by non-covalent binding, and most of them are used for treatment for Alzheimer’s Disease. Applying those inhibitors as pesticide, we can greatly reduce the damage for the environment. In this thesis, we study on the selectivity of TZ2PA6as acetylcholinesterase inhibitors in different species to uncover the molecular mechanism of the selectivity, and lay the foundation for the design of selective acetylcholinesterase inhibitors.In the thesis, we built the six complexes, three different origin of acetylcholinesterases, mouse, Torpedo and Drosophila Melanogaster acetylcholinesterase respectively, bind with synl and antil, then utilize molecular modeling methods to explor the interactions between the ligands and receptors. In the three acetylcholinesterases, the type I includes mouse and Torpedo acetylcholinesterase, and the type II includes Drosophila Melanogaster acetylcholinesterase. According to energies decomposition, we conclude that three complexes have similar interactions in the catalytic anionic sites. Because there is difference in the linker in synl and antil, they have different length of the linkers, which result in the different binding model in the peripheral anionic site. In the synl and mouse as well as Torpedo acetylcholinesterase complexes, there are sandwiched π-π stackings, however, antil just formed one π-π stacking, which is the reason for different activity. Meanwhile, the peripheral anionic site is the place the cause the selectivity. In the mouse and Torpedo acetylcholinesterase, they have similar structure in the peripheral anionic site, the residue Tyr72(mouse acetylcholinesterase) and Tyr67 (Torpedo acetylcholinesterase) have different orientation with Tyr71in the Drosophila Melanogaster acetylcholinesterase, which is the reason that selectivity generates.