[en] Highlights: • We investigated specific interactions between APP peptide and curcumin derivatives. • Electronic states were evaluated by ab initio fragment molecular orbital method. • New curcumin derivative suppressing Aβ42 production was proposed. • The oxygen atom of central part of curcumin is important for binding to APP. • Hydrophobic Ile9, Met12, Val13 and Val16 of APP contribute to binding with curcumin. Accumulation of amyloid-β (Aβ) peptides in a brain is closely related with the pathogenesis of Alzheimer's disease. To suppress the production of Aβ peptides, we propose novel curcumin derivatives and investigate their binding properties with the amyloid precursor protein (APP), using protein-ligand docking as well as ab initio molecular simulations. Our proposed derivative (curcumin XIV) is found to have a large binding energy with APP and interacts strongly with the cleavage site Ala19 by secretase. It is thus expected that curcumin XIV can protect APP from the secretase attack and be a potent inhibitor against the production of Aβ peptides.