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The Significance of Protein Structure Data Set Choices for in-silico Drug Discovery: Design of BACE1 Inhibitors

Monday, 24 March 2014 15:39
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Yoshio Hamada
Dr Yoshio Hamada gave this presentation at the International Symposium on Compound Design Technologies held in Tokyo and Osaka, Japan on 19 and 20 March 2014.

In this lecture, I will discuss the significance of protein X-ray crystal structure data set choices for in-silico drug design/screening, using our drug discovery research on BACE1 inhibitors as an example. β-Secretase, also called BACE1 (β-site APP amyloid precursor protein cleaving enzyme 1) is a molecular target for developing Alzheimer’s disease (AD) drugs. BACE1 triggers the formation of amyloid β peptide (Aβ), which is the main component of senile plaques in the brains of AD patients, and is recognized as the causative agent of AD. BACE1 recognizes the EVKM*D sequence and cleaves amyloid precursor protein (APP) on the N-terminal side of the Aβ domain to produce Aβ. Swedish-mutant APP is found in familial AD patients and its cleavage site is mutated to the EVNL*D sequence, which is cleaved faster than the wild-type sequence is by BACE1. Ghosh et al reported the first X-ray crystal structure (1FKN) of BACE1 in a complex with an inhibitor (OM99-2) that was designed based on the Swedish-mutant sequence. The 1FKN structure showed that the Arg235 side chain of BACE1 interacted with the P2 side chain (Asn) of OM99-2 by hydrogen bonding. Many researchers, including our group, have reported BACE1 inhibitors that are based on the Swedish-mutant sequence and are designed using this crystal structure data set for docking calculation. However, we previously reported that most inhibitors complexed with BACE1, with the exception of OM99-2, and interacted with the Arg235 side chain of BACE1 by quantum chemical interactions such as σ-π interactions and not by hydrogen bonding. Furthermore, I found that such quantum chemical interactions are important for BACE1 inhibition. These findings indicated that the concepts for designing substrates and inhibitors are fundamentally different. Therefore, I proposed an “electron donor/acceptor bioisostere” medicinal science concept based on quantum chemical interactions, and applied it to design the first peptides with BACE1 inhibitory activity.

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