| 초록 |
The pathogenesis of Alzheimer’s disease is intimately related to the presence of the neurotoxic amyloid-β peptide (Aβ) in the brain. A key step in the production of Aβ is the cleavage of a membrane protein called the amyloid precursor protein by a protease known as β-secretase. Recently, Kiso and co-workers have synthesized highly potent β-secretase inhibitors, KMI-420 and KMI-429, which contain two amino acid residues and three amino acid analogs. In this work, using the CHARMM program, we have generated the structures of the inhibitors and energy-minimized them while constraining the 3-D structure of the binding site of β-secretase. In order to elucidate the origin of binding affinity of the inhibitors, binding energies of the inhibitors with β-secretase have been calculated and analyzed in terms of nonpolar and polar interactions. It is revealed that the large side chains at P4 and P1’ sites of the inhibitors are crucial for the enhanced binding affinity. |
