Destabilization of Alzheimer's Aβ42 Protofibrils with a Novel Drug Candidate wgx-50 by Molecular Dynamics Simulations

Alzheimer's disease (AD) is one of the most common dementia. The aggregation and deposition of the amyloid-beta peptide (A beta) in neural tissue is its characteristic symptom. To destabilize and dissolve A beta fibrils, a number of candidate molecules have been proposed. wgx-50 is a compound extracted from Sichuan pepper (Zanthoxylum bungeanum) and a potential candidate drug for treating AD. Our early experiments show it is effective in disassembling A beta 42 aggregations. A series of molecular dynamics simulations were performed in this work to explain the molecular mechanism of the destabilization of A beta 42 protofibril by wgx-50. It is found that there were three possible stable binding sites including two sites in hydrophobic grooves on surface of A beta protofibril that made no significant changes in A beta structures and one site in the interior that caused destabilization of the protofibril. In this site, wgx-50 was packed against the side chains of 132 and L34, disrupted the D23-K28 salt bridges, and partially opened the tightly compacted two beta-sheets. The results were confirmed by simulations at 320 K, where deeper insertion of wgx-50 into the whole protofibril was observed. The molecular mechanism of this novel drug candidate wgx-50 to disaggregate A beta protofibril may provide some insight into the strategy of structure-based drug design for AD.