The Simulation Study On The Interaction Of WGX-50 With Amyloid-? Peptide

Alzheimer's disease(AD)is one of the most common dementia.The aggregation and deposition of the amyloid-?peptide(A?)in neural tissue is its characteristic symptom.In order to destabilize and dissolve A?fibrils,a number of researchs have been proposed.WGX-50 is a compound extracted from Sichuan pepper(Zanthoxylum bungeanum),and a potential candidate drug for treating Alzheimer's disease(AD).Our early experiments show it is effective in disassembling A?₄₂ aggregations.To explain the molecular mechanism of the destabilization of A?₄₂ by WGX-50,a series of molecular dynamics simulations were performed in this work.First,we constructed A?pentamer+WGX-50 complex system.It is found that there were three possible stable binding sites including two sites in hydrophobic grooves on surface of A?pentamer that made no significant changes in A?structures,and one site in the interior that caused destabilization of A?pentamer.Therefore,it is reasonable to assume the possible role of WGX-50 in anti-aggregation of A?.WGX-50 is inserted into the interior site C,causes significant deformation of the cross-?subunit and stops assembly of the A?fibril.In this site,WGX-50 was packed against the side chains of Ile32 and Leu34,disrupted the Asp23-Lys28 salt bridges,and partially opened the tightly compacted two?-sheets.The results were confirmed by simulations at 320 K,where deeper insertion of WGX-50 into the whole pentamer was observed.Then,we constructed A?annular channel+WGX-50 complex system in DOPC bilayer.MD simulation results of wild system are in consistent with former studies that the outer and pore diameter in the?6-8 and?1-2 nm range,respectively.While the complex system decreased inner pore dramatically,suggesting great destabilization by WGX-50.In agreement with previous studies,the wild system formed a cationic ring near the negatively charged Glu22.However,WGX-50 apparently weakened the interaction of Glu22 with Ca²⁺,inhibiting Ca²⁺flux across the A?channel.The main innovation is that the molecular mechanism of this novel drug candidate WGX-50 to inhibit A?aggregation in different conditions may provide some insight on the strategy of structure-based drug design for Alzheimer's disease.