Fragment-based discovery of nonpeptidic BACE-1 inhibitors using tethering
| Autor: | Douglas R. Cary, Jennifer Wilkinson, Yafan Lu, Robert S. McDowell, Phuongly Pham, Jeffrey W. Jacobs, Wanli Lu, Melissa B Lam, Michael J. Romanowski, Beth Pietrak, Marcus Ballinger, Raymond V. Fucini, Jian Sun, David M Penny, Wenjin Yang, Timothy J. Allison, Mike Randal, Dennis Colussi, Anila E Thomas, Bruce T. Fahr, Kenneth E Lind, Sanjeev Munshi |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Stereochemistry Drug Evaluation Preclinical Molecular Conformation Ligands Biochemistry Structure-Activity Relationship Piperidines Catalytic Domain Drug Discovery Amyloid precursor protein Moiety Structure–activity relationship Humans Cysteine Enzyme Inhibitors chemistry.chemical_classification biology Chemistry Drug discovery Active site Small molecule Enzyme Mutation biology.protein Biocatalysis Amyloid Precursor Protein Secretases Peptides |
| Zdroj: | Biochemistry. 48(21) |
| ISSN: | 1520-4995 |
| Popis: | BACE-1 (beta-site amyloid precursor protein cleaving enzyme), a prominent target in Alzheimer's disease drug discovery efforts, was surveyed using Tethering technology to discover small molecule fragment ligands that bind to the enzyme active site. Screens of a library of >15000 thiol-containing fragments versus a panel of BACE-1 active site cysteine mutants under redox-controlled conditions revealed several novel amine-containing fragments that could be selectively captured by subsets of the tethering sites. For one such hit class, defined by a central aminobenzylpiperidine (ABP) moiety, X-ray crystal structures of BACE mutant-disulfide conjugates revealed that the fragment bound by engaging both catalytic aspartates with hydrogen bonds. The affinities of ABP fragments were improved by structure-guided chemistry, first for conjugation as thiol-containing fragments and then for stand-alone, noncovalent inhibition of wild-type (WT) BACE-1 activity. Crystallography confirmed that the inhibitors bound in exactly the same mode as the disulfide-conjugated fragments that were originally selected from the screen. The ABP ligands represent a new type of nonpeptidic BACE-1 inhibitor motif that has not been described in the aspartyl protease literature and may serve as a starting point for the development of BACE-1-directed Alzheimer's disease therapeutics. |
| Databáze: | OpenAIRE |
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