Insights into the Inhibitory Mechanism of Dicyanovinyl‐Substituted J147 Derivative against Aβ ₄₂ Aggregation and Protofibril Destabilization: A Molecular Dynamics Simulation Study

Abstract

Abstract The self‐assembly of amyloid β‐peptide (Aβ) into β‐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 Aβ aggregation. Previous studies reported that compound C1 (J147 derivative) strongly inhibit Aβ aggregation and disassemble preformed fibrils, however, the underlying inhibitory mechanism remains elusive. In this regard, the molecular mechanism behind the anti‐aggregation 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 Aβ 42 monomer and inhibit its conformational transition into aggregation prone β‐conformation. C1 destabilize Aβ 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 Aβ 42 protofibril. The present study provides a complete picture of the inhibitory mechanism of C1 against Aβ 42 oligomer formation and fibril disassembly.