Drug Discovery of β-Secretase Inhibitors Based on Quantum Chemical Interactions for the Treatment of Alzheimer's Disease

Abstract

Alzheimer’s disease, which is the most common cause of dementia, is characterized by progressive intellectual deterioration. According to the amyloid hypothesis, a transmembrane aspartic protease, β-secretase (BACE1), is a promising molecular target for development anti-Alzheimer drugs. This protease triggers amyloid β (Aβ) formation, which is involved in the development of Alzheimer’s disease. Many research groups have shown various BACE1 inhibitors to be efficacious in the treatment of Alzheimer’s disease. Given the fact that Swedish-mutant amyloid precursor protein (APP) is cleaved faster than wild-type APP, early BACE1 inhibitors were designed on the basis of the Swedish-mutant APP amino acid sequence and possess a substrate transition-state analogue. At an early stage of this research, we also reported a series of peptidic BACE1 inhibitors possessing a substrate transition-state analogue. Subsequently, nonpeptidic BACE1 inhibitors were designed using the peptidic inhibitors as lead compounds and an in-silico conformational structure-based drug design approach. These inhibitors showed potent inhibitory activities. Among these, some inhibitors exhibited effective BACE1 inhibition in cultured cells and significant reduction of Aβ production in vivo. In the process, we found that a quantum chemical interaction between the inhibitors and an arginine side chain at the active site of BACE1 plays a crucial role in the mechanism of BACE1 inhibition. In fact, out of the publicly available X-ray crystal structures of BACE1-inhibitor complexes, most interact with the Arg235 side chain of BACE1 by a quantum chemical interaction. It is known that quantum chemical interactions involving an arginine side chain play an important role in molecular recognition in proteins. Hence, a series of potent BACE1 inhibitors that were optimized to focus on the quantum chemical interaction with the arginine side chain of BACE1 were designed. Furthermore, based on these quantum chemical interactions, we proposed a novel concept in medicinal science, the electron donor/acceptor bioisostere. Although the bioisostere is an important concept in the design of practical drugs, the classical bioisostere concept does not assume interactions by such quantum chemical effects. This review describes our peptidic BACE1 inhibitors produced using substrate-based design and non-peptidic BACE1 inhibitors produced using structure-based design approaches. Subsequently, the significance of quantum chemical interaction in medicinal chemistry is discussed, and potent small-sized BACE1 inhibitors and the first peptides with BACE1 inhibitory activities, which were designed based on quantum chemical interactions, are described.