Insights into the Inhibitory Mechanism of Dicyanovinyl-Substituted J147 Derivative against Aβ42 Aggregation and Protofibril Destabilization: A Molecular Dynamics Simulation Study

The self-assembly of amyloid b-peptide (Ab) into beta-sheet enriched fibrillar aggregates is associated with Alzheimer's disease (AD). A disease modifying therapy for AD involves a search for inhibitors that can inhibit Ab aggregation. Previous studies reported that compound C1 (J147 derivative) strongly inhibit Ab aggregation and disassemble preformed fibrils, however, the underlying inhibitory mechanism remains elusive. In this regard, the molecular mechanism behind the antiaggregation activity of C1 has been investigated using molecular docking and molecular dynamics (MD) simulations. C1 effectively binds to central hydrophobic core (CHC) region i.e. KLVFF (16-20) of A beta(42) monomer and inhibit its conformational transition into aggregation prone b-conformation. 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 A beta(42) protofibril. The present study provides a complete picture of the inhibitory mechanism of C1 against A beta(42) oligomer formation and fibril disassembly.