Mechanism Of Edaravone And Newly Designed Hexapeptides Inhibiting Aggregation Of Beta-amyloid(Aβ)

Alzheimer’s disease is a serious illness threating the health of old people. According to the Amyloid Cascade Hypothesis, the generation of Aβ aggregates is an important pathogenic factor of AD. A feasible therapeutic schedule for AD is to inhibit aggregation of Aβ and decrease aggregates of Aβ. Edaravone could inhibit aggregation of Aβ and depolymerize Aβ aggregates, and this ability is an important reason why edaravone has therapeutic effect. Several hexapeptides with ability to inhibit aggregation of Aβ have been designed in our previous work. But mechanisms of edaravone and newly designed hexapeptides are unclear and difficult to be studied by traditional experimental methods. Inhibitory mechanisms of edaravone and newly designed hexapeptides, including CTIYWG, CTLWWG and GTVWWG, to aggregation of Aβ were researched by molecular simulation in this study.This study provided the possible inhibitory mechanisms of edaravone and newly designed hexapeptides and deepened the understanding of inhibitory process of inhibitors. Simultaneously, this work offered theoretical support for study of inhibitors and was beneficial to the screening and design of new inhibitors.The main research contents and results are as follows:(1)The most likely acting site on Aβ pentamer of edaravone was searched by molecular docking, and the conformation with the lowest binding energy in 1000 combinative conformations was regarded as the structure of complex composed of Aβ pentamer and edaravone. Then the structure of complex was optimized by quantum chemical calculation. Through the analysis of structural influence on Aβ pentamer caused by edaravone, inhibitory mechanism of edaravone was studied. The results showed that edaravone could bond to the central hydrophobic region of Aβ pentamer, and then weaken the binding force between neighboring monomers of Aβ pentamer. Edaravone could depolymerize Aβ pentamer, inhibit generation of Aβ fibrils, and decrease toxicity of cell by this way.(2)First, the interaction between newly designed hexapeptides and Aβ monomer was studied by quantum chemistry calculation, and inhibitory mechanisms of three hexapeptides were researched according to the comparision of interaction energy. Then molecular docking method was used to search the most likely acting site on Aβ pentamer of three hexapeptides. Finally, the interaction between hexapeptides and Aβ pentamer was researched by molecular dynamics simulation in 100 ns, and inhibitory mechanisms were studied according to the analysis of structural influences on Aβ pentamer caused by three hexapeptides. The results indicated that newly designed hexapeptides could interact with fragments KLVFFA and NKGAII of Aβ monomer, and competitively inhibit the combination of Aβ monomers, and decrease the toxicity of cell. Three hexapeptides also could bond to L17-V21 region of Aβ pentamer, and then inhibit the enlongation of Aβ pentamer and the formation of Aβ fibril. CTIYWG could make C-termination residues of strand A and B interact with I32-V36 region of strand E. This disturbed enlongation of β-sheet in I32-V36 region and hampered accumulation, through the connection of β-sheet, of Aβ pentramer, and weakened combinative interaction between Aβ oligomers. CTLWWG could weaken combinative interaction between neighboring monomers and fracture β-sheet structure in the C-termination region of Aβ pentamer. This ability to depolymerize Aβ pentamer is one way of inhibiting formation of Aβ fibrils and decreasing toxicity of cell. GTVWWG could stabilize combination of strands at the side that it bonded and destabilize combination of strands at the other side. It competitively occupied the position needed by elongation of Aβ pentamer at the side it bonded and limited the ability for enlongation of Aβ pentamer at the other side. This is one way of inhibiting generation of Aβ fibril.