Insights into the inhibitory mechanism of a resveratrol and clioquinol hybrid against Aβ 42 aggregation and protofibril destabilization: A molecular dynamics simulation study.

Amyloid-β (Aβ) peptide instinctively aggregate and form plaques in the brain of Alzheimer's disease (AD) patients. At present, there is no cure or treatment for AD, and significant effort has, therefore, been made to discover potent drugs against AD. Previous studies reported that a resveratrol and clioquinol hybrid compound [(E)-5-(4-hydroxystyryl)quinolone-8-ol], C1, strongly inhibit Aβ42 aggregation and disassemble preformed fibrils. However, the atomic level details of the inhibitory mechanism of C1 against Aβ42 aggregation and protrofibril disassembly remains elusive. In this regard, molecular docking and molecular dynamics (MD) simulation of Aβ42 monomer, Aβ42 monomer-C1 complex, Aβ42 protofibril, and Aβ42 protofibril-C1 complex were performed in the present study. MD simulations highlighted that C1 bind in the central hydrophobic core (CHC) region, i.e., KLVFF (16-20) of Aβ42 monomer, which plays a critical role in Aβ42 aggregation. C1 promote the formation of native helical conformation in the Aβ42 monomer and decrease the probability of D23-K28 salt bridge interaction that is critical in the formation of aggregation-prone β-sheet conformation. Further, C1 destabilize Aβ42 protofibril structure by increasing the interchain distance between chains A-B, disrupting the salt-bridge interaction between D23-K28, and decreasing the number of backbone hydrogen bonds between chains A-B of the Aβ42 protofibril structure. The insights into the underlying inhibitory mechanism of small molecules that display potential in vitro anti-aggregation activity against Aβ42 will be beneficial for the rational design of more potent drug molecules against AD. Communicated by Ramaswamy H. Sarma.