Design of anti-alzheimer’s disease agents focusing on a specific interaction with target biomolecules

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive intellectual deterioration. Amyloid β peptide (Aβ), the main component of senile plaques in the brains of patients with AD, is formed from amyloid precursor protein (APP) by two processing enzymes. According to the amyloid hypothesis, a processing enzyme β-secretase (BACE1; β-site APP cleaving enzyme) that triggers Aβ formation in the rate-limiting first step of Aβ processing appears to be a promising molecular target for therapeutic intervention in AD. Many researchers have revealed BACE1 inhibitors for the AD treatment. Early BACE1 inhibitors were designed based on the first reported X-ray crystal structure, 1FKN, of a complex between recombinant BACE1 and inhibitor OM99-2. Although OM99-2 seemed to interact with BACE1-Arg235 side chain by hydrogen bonding, we found that a quantum chemical interaction, such as σ-π interaction or π-π stacking, plays a critical role in BACE1 inhibition mechanism. Moreover, we proposed a novel “electron-donor bioisostere” concept in drug discovery study and designed potent BACE1 inhibitors using this concept.