Insights into the inhibitory mechanism of a resveratrol and clioquinol hybrid against Aβ42 aggregation and protofibril destabilization: A molecular dynamics simulation study

Amyloid-beta (A beta) 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 A beta(42) aggregation and disassemble preformed fibrils. However, the atomic level details of the inhibitory mechanism of C1 against A beta(42) aggregation and protrofibril disassembly remains elusive. In this regard, molecular docking and molecular dynamics (MD) simulation of A beta(42) monomer, A beta(42) monomer-C1 complex, A beta(42) protofibril, and A beta(42) 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 A beta(42) monomer, which plays a critical role in A beta(42) aggregation. C1 promote the formation of native helical conformation in the A beta(42) monomer and decrease the probability of D23-K28 salt bridge interaction that is critical in the formation of aggregation-prone beta-sheet conformation. Further, C1 destabilize A beta(42) 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 A beta(42) protofibril structure. The insights into the underlying inhibitory mechanism of small molecules that display potential in vitro anti-aggregation activity against A beta(42) will be beneficial for the rational design of more potent drug molecules against AD. [GRAPHICS] .