Inhibitory Mechanisms of Three Modified Small Molecules on the Misfolding of Cu2+‐Aβ42 Complex in Different pH Conditions: Insights from MD/QM Studies.

The paper reports in silico three modified small molecules, two negatively charged E1C and E2C and one neutral TQ, which show more potent inhibitory effect than their parental molecules CQ3, TS0, and ER on the Cu2+ induced Aβ42 aggregation. In the acidic condition, TQ is the most powerful inhibitor, as it not only decreases the helix content of Cu2+‐Aβ42 complex but also increases the oxidizability; E1C/E2C however decreases the helix content of Cu2+‐Aβ42 complex but also with increased oxidizability, indicating that the inhibitory effect of the two charged molecules depends on the multiple factors, at least including the composite mechanism of helix decrease and oxidizability increase. In the basic condition, any of three modified molecules can increase the helix content of the Cu2+‐Aβ42 complex. Anyway, small molecules containing neutral and larger hydrophobic aromatic groups are always more effective in inhibiting Cu2+‐induced Aβ42 aggregation in both basic and acidic conditions. [ABSTRACT FROM AUTHOR]