Identification of a Small Molecule Nonpeptide Active Site β-Secretase Inhibitor That Displays a Nontraditional Binding Mode for Aspartyl Proteases

Coburn, Craig A.; Stachel, Shawn J.; Li, Yueming; Rush, Diane M; Steele, T. G.; Chen-Dodson, Elizabeth; Holloway, M. Katharine; Xu, Min; Huang, Qian; Lai, Ming‐Tain; DiMuzio, Jillian; Crouthamel, Ming-Chih; Shi, Xiao‐Ping; Sardana, Vinod; Chen, Zhongguo; Munshi, Sanjeev; Kuo, Lawrence C.; Makara, Gergely M.; Annis, D. Allen; Tadikonda, Praveen K.; Nash, Huw M.; Vacca, Joseph P.; Wang, Tong

doi:10.1021/jm049388p

Cited by 118 publications

(113 citation statements)

References 17 publications

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“…Compounds 10 and 11, which contain the substituent, did show nanomolar activities. The unexpected results pushed us to carefully study the complex crystal structures of 3 and 4 [14,15,23,24] . Coburn provided a possible explanation for the unexpected phenomena [23] that the α-methyl of (4-fluorophenyl)ethyl of 3 at the 3-position packs firmly against Ile110 of BACE-1, which orients the 4-fluorophenyl ring toward S 3 and creates a novel S 3 subpocket (S 3 SP ).…”

Section: Discussionmentioning

confidence: 99%

“…The unexpected results pushed us to carefully study the complex crystal structures of 3 and 4 [14,15,23,24] . Coburn provided a possible explanation for the unexpected phenomena [23] that the α-methyl of (4-fluorophenyl)ethyl of 3 at the 3-position packs firmly against Ile110 of BACE-1, which orients the 4-fluorophenyl ring toward S 3 and creates a novel S 3 subpocket (S 3 SP ). The subpocket is unique, different from other reported BACE-1 complexed structures, which may make (4-fluorophenyl) ethyl as a suitable substituent as R 3 , even for HE-based inhibitors [14,15] , although it is relatively large for the S 3 pocket.…”

Section: Discussionmentioning

confidence: 99%

“…Merck's group previously found a nonpeptidomimetic BACE-1 inhibitor 3 ( Figure 2) through high-throughput screening and lead optimization [23] . The group also disclosed the crystal structure of the inhibitor bound to the enzyme, which showed that the molecule occupied the S 1 -S 4 subsites of BACE-1, but lacked direct interaction with the catalytic aspartates of the enzyme; this is presumed to be a main cause of its moderate activity.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

Zhu

Xiao

et al. 2009

Acta Pharmacol Sin

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Aim:The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease β-secretase (BACE-1) bearing hydroxyethylene (HE) framework.Methods: First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode. Results:Thirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low-and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. Conclusion:This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

Zhu

Xiao

et al. 2009

Acta Pharmacol Sin

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“…A small compound (molecular weight [MW] = 506) was identified with an IC 50 of 25 mM. 42 In another application of ALIS in which 356,474 compounds were screened, both orthosteric and allosteric antagonists were discovered for muscarinic M2 acetylcholine receptor, a G-proteincoupled receptor. Their activity was confirmed in a biochemical assay.…”

Section: Mass Spectrometrymentioning

confidence: 99%

High-Throughput Affinity-Based Technologies for Small-Molecule Drug Discovery

Zhu¹,

Cuozzo²

2009

SLAS Discovery

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High-throughput affinity-based technologies are rapidly growing in use as primary screening methods in drug discovery. In this review, their principles and applications are described and their impact on small-molecule drug discovery is evaluated. In general, these technologies can be divided into 2 groups: those that detect binding interactions by measuring changes to the protein target and those that detect bound compounds. Technologies detecting binding interactions by focusing on the protein have limited throughput but can reveal mechanistic information about the binding interaction; technologies detecting bound compounds have very high throughput, some even significantly higher than current high-throughput screening technologies, but offer limited information about the binding interaction. In addition, the appropriate use of affinity-based technologies is discussed. Finally, nanotechnology is predicted to generate a significant impact on the future of affinity-based technologies. (Journal of Biomolecular

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“…Primary hits are usually identified and validated solely based on reproducible binding to the target protein and not on a secondary event, such as enzymatic activity or competitive displacement of a reporter. Although AS-MS screening technologies have been successfully used to discover and characterize small-molecule ligands to proteins of various drug target classes, [10][11][12][13][14][15] these techniques have not yet been routinely applied to screening of integral membrane proteins.…”

mentioning

confidence: 99%

Discovery and Characterization of Orthosteric and Allosteric Muscarinic M2 Acetylcholine Receptor Ligands by Affinity Selection–Mass Spectrometry

Whitehurst¹,

Nazef²,

Annis³

et al. 2006

SLAS Discovery

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Screening assays using target-based affinity selection coupled with high-sensitivity detection technologies to identify smallmolecule hits from chemical libraries can provide a useful discovery approach that complements traditional assay systems. Affinity selection-mass spectrometry (AS-MS) is one such methodology that holds promise for providing selective and sensitive high-throughput screening platforms. Although AS-MS screening platforms have been used to discover smallmolecule ligands of proteins from many target families, they have not yet been used routinely to screen integral membrane proteins. The authors present a proof-of-concept study using size exclusion chromatography coupled to AS-MS to perform a primary screen for small-molecule ligands of the purified muscarinic M 2 acetylcholine receptor, a G-protein-coupled receptor. AS-MS is used to characterize the binding mechanisms of 2 newly discovered ligands. NGD-3350 is a novel M 2 -specific orthosteric antagonist of M 2 function. NGD-3366 is an allosteric ligand with binding properties similar to the allosteric antagonist W-84, which decreases the dissociation rate of N-methyl-scopolamine from the M 2 receptor. Binding properties of the ligands discerned from AS-MS assays agree with those from in vitro biochemical assays. The authors conclude that when used with appropriate small-molecule libraries, AS-MS may provide a useful high-throughput assay system for the discovery and characterization of all classes of integral membrane protein ligands, including allosteric modulators. (Journal of Biomolecular

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Identification of a Small Molecule Nonpeptide Active Site β-Secretase Inhibitor That Displays a Nontraditional Binding Mode for Aspartyl Proteases

Cited by 118 publications

References 17 publications

Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

Discovery of potent β-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids

High-Throughput Affinity-Based Technologies for Small-Molecule Drug Discovery

Discovery and Characterization of Orthosteric and Allosteric Muscarinic M2 Acetylcholine Receptor Ligands by Affinity Selection–Mass Spectrometry

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