Abstract
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.
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Acknowledgment
The study was supported in part by the Grants-in-Aid for Scientific Research from MEXT (Ministry of Education, Culture, Sports, Science and Technology), Japan (KAKENHI No. 23590137 and No. 26460163), and the donation from Professor Emeritus Tetsuro Fujita of Kyoto University. At the time writing, we received word that Prof. Fujita had passed away on January 1, 2017. Prof. Fujita was the teacher of one of the authors, Y. Hamada, and was known as the inventor of a treatment agent for multiple sclerosis. We dedicate this article to Prof. Fujita.
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Hamada, Y., Usui, K. (2018). Design of Anti-Alzheimer’s Disease Agents Focusing on a Specific Interaction with Target Biomolecules. In: Roy, K. (eds) Computational Modeling of Drugs Against Alzheimer’s Disease. Neuromethods, vol 132. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7404-7_8
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DOI: https://doi.org/10.1007/978-1-4939-7404-7_8
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