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

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. You can download this presentation as a PDF .