Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates

Bowers, Simeon; Xu, Yinchuan; Shuanggui, Yuan; Probst, Gary D.; Hom, Roy K.; Chan, Wayman; Konradi, Andrei W.; Sham, Hing L.; Zhu, Yong; Beroza, Paul; Pan, Hongyu; Brecht, E.; Yao, Nanhua; Lougheed, Julie C.; Tam, Danny; Zhao, Rongjun; Ruslim, Lany; Bova, Michael P.; Artis, Dean R.

doi:10.1016/j.bmcl.2013.01.103

Cited by 11 publications

(9 citation statements)

References 27 publications

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“…6 ) registered a compelling Biacore sensorgram trace with a calculated K d of 62 µM and formed a co-crystal structure with BACE. 29 Lead optimization efforts on compound 1 are highlighted elsewhere and are beyond the scope of this report. 29 In addition, as expected, a number of compounds based on the HEA scaffold emerged as hits from the HTS campaign, which served to further validate the assay and screen (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Development of a Novel β-Secretase Binding Assay Using the AlphaScreen Platform

Zhao

Tam

et al. 2013

SLAS Discovery

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Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. β-secretase-1 (BACE1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Aβ is a validated target for AD. Herein, the authors develop and validate a novel binding assay for BACE1 using the AlphaScreen platform that is amenable for highthroughput screening (HTS). Small-molecule BACE1 inhibitors of the hydroxyethylamine, hydantoin, and sulfamide classes were functionalized by biotin PEG linkers of varying lengths forming probes that were bound to streptavidin donor beads. BACE1 was coupled to nickel-chelate acceptor beads. Upon mixing, probes designed from all three classes registered high signal-to-background values in the AlphaScreen binding assay, where the interaction between probe and BACE1 was completely blocked by free parent compound. A probe from the hydantoin class was chosen for further optimization, where the final assay conditions of 50 nM BACE and 250 nM probe were used and Z ′ values >0.75 were commonly observed. IC 50 values determined by the AlphaScreen assay format exhibited ~10-fold greater sensitivity when compared with a fluorescence polarization-based activity assay. The assay was miniaturized to a 1536-well format for HTS, in which 525 000 compounds were screened.

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Section: Resultsmentioning

confidence: 99%

Development of a Novel β-Secretase Binding Assay Using the AlphaScreen Platform

Zhao

Tam

et al. 2013

SLAS Discovery

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“…For example, the same substructure fully interacts with two catalytic residues (e.g., PDB code: 2HM1, IC 50 = 2 nM, Figure b) or partially interacts with two catalytic residues (e.g., PDB code: 3CIB, IC 50 = 14 nM, Figure S3b). The other case is that the ligand does not contain the preferred substructures to match the subsite (e.g., PDB code: 4HZT, IC 50 = 750 nM).…”

Section: Preferred Substructure Of Inhibitors For Each Subsitementioning

confidence: 99%

“…The binding orientation of the ligands in group L11 is perpendicular to most ligands (e.g., PDB code: 5ENM, IC 50 = 70 nM 85 ) which lie down on the pocket. Group L12 includes few ligands with unusual binding position which is located at very edge of the pocket and far away from the catalytic aspartic residues (e.g., PDB code: 4I10, IC 50 = 170 nM 58 ). Therefore, ligands in the L1−L4 groups (L1−L4) interacting with different subsites of the 8-like region reveal four major binding modes of inhibitors, providing a foundation to understand better the preference of BACE1 in ligand recognition.…”

Section: Classification Of Ligands Based On Subsite Occupationmentioning

confidence: 99%

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Structure-Based Survey of the Binding Modes of BACE1 Inhibitors

Chen

et al. 2018

ACS Chem. Neurosci.

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BACE1 is a key aspartic protease that cleaves the amyloid precursor protein to generate of the amyloid peptide that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus recognized as a promising therapeutic target for Alzheimer's disease treatment, and large efforts have been made in the discovery of novel BACE1 inhibitors. This Review presents a systematic mining of BACE1 inhibitors based on 354 crystal structures of the BACE1 catalytic domain in complex with ligands in the Protein Data Bank. A thorough exploration on the frequency as well as the patterns of residue−ligand interactions enables us to subdivide the ligand binding pocket into 10 subsites and then identify favorable substructures of ligands for each subsite. In addition, it is found that the assembly of subsites with an 8like shape is responsible to bind all inhibitors and four major ligand binding modes are revealed. Thus, such a systematic survey deepens our understanding of the structural requirements for establishment of BACE1−ligand interactions that determine the affinity of a ligand to BACE1, which is pivotal for structure-based lead optimization and design of novel inhibitors.

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“…As a class of cyclic amidine compounds, 1-amino-3,4-dihydroisoquinolines are essential six-membered heterocycles which can be found in numerous natural products, functional chemicals and pharmaceutical agents ( Scheme 1 ). 1 For example, piperazine tethered dihydroisoquinoline and benzocyclic amide I was found to be an efficient cardiovascular agent. 1 a Phenylalanine-derived and arylamine or cyclic aliphatic-amine-containing 1-amino-3,4-dihydroisoquinolines (II–V) show outstanding BACE-1 inhibition, kinase VEGFR-2 inhibition, phosphodiesterase IV inhibition and hydrogen ion-sodium exchanger NHE-3 inhibition activities, respectively.…”

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confidence: 99%