| Alzheimer disease (AD) is a neurodegenerative disorder of the central nervous system. It is recognized as a major public health problem having a severe impact on human beings. Its major pathological signs: p-amyloid plaques, neurofibrillary tangles and synaptic loss. Because the AD syndrome has multiple molecular causes and a gradual, chronic evolution, the etiologies and the shared biochemical mechanism of this syndrome have been so difficult to identify. This paper is to focus on exploring the mechanisms of two genetic defects that are already known to cause AD by molecular modeling. A deficiency in cholinergic neurotransmission is considered to be one of the major causes of memory impairments in patient. Acetylcholinesteras (AChE) inhibitors can restore the level of acetylcholine and then enhance memory. Here, we have carried out the drug design of AChE inhibitors on the basis of the crystal structure of AChE; another of major pathological characters is that senile plaques (SPs) occur in the brains of patients. SPs are neurotoxic and their extensive depositions cause neurodegeneration. The studies show that Amyloid p-peptides (Aps) aggregate and accumulate, moreover, colocalize with numerous other associated protein and nonprotein components to form SPs. There are many factors to induce the Ap aggregation. Here, we have studied the mechanism of Zn2+ ions inducing the aggregation of Ap. For the above two aspects, the following work were done:1. Tacrine, the first drug for AD, has shown efficacy in delaying the deterioration of the symptoms of AD, however, its severe side effects, such as hepatotoxicity and gastrointestinal upset. In order to develop new and potentially more effective classes of Tacrine derivatives, we established a new approximate method calculating binding free energy to predict the relative affinities of the derivatives. The binding free energy calculations by the following equation:In first equation, the left parenthesis denotes the absolute free energies associated with complex system Gcomplex and unbound protein Gprotein, respectively, while the right parenthesis contains solvated inhibitor Ginh+water and solvent water Gwater. (△Ginh)protein represents the absolute free energy of inhibitor in protein-solventenvironment; (△Ginh)water represents the absolute free energy of inhibitor in only-solvent environment. In the case, △Gbind approximately equals to the free energy change of inhibitor from water environment to protein environment.2. Tacrine-huperzine A hybrid (Huperzine X) was regarded as a valuable candidates in second era for the palliative treatment of Alzheimer's diease. In order to save computer time and resources, we improved on the above proposal calculating binding free energy. The free energy of binding was cast simply as a linear combination of three descriptors: interaction energy between inhibitors and protein, the difference in the absolute conformation free energy of protein in the bound and unbound states, the free energy change of inhibitors from the minimization conformation to activity conformation. For the relative affinities of 14 Huperzine X derivatives, the result obtained from the method was found to correlate well with the experimental active data (IC50), the Spearman's correlation coefficient, rs= 0.85. Subsequently, we applied the practical proposal to design some novel Huperzine X derivatives.3. Zn2+ ion induces significant Aβ aggregation at nearly physiological concentrations in virtro. In order to explore the induce mechanism, in this paper the possible binding modes of Zn2+ in Ap peptide were firstly studied by molecular modeling method. Modeling results showed that in soluble Zn2 + complex, NT of imidazole ring of His 14, O of carbonyl of main-chain, and two O of water occupy the four ligand positions of the tetrahedral complex; in the aggregation of Aβ, the His 13(Nτ)- Zn2+-Hisl4(NT) bridges are formed by Zn2+ cross-linking action. The possible Zn2+ binding mode obtained by the studies will be helpful to...
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