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Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta.

Jiang L, Liu C, Leibly D, Landau M, Zhao M, Hughes MP, Eisenberg DS - Elife (2013)

Bottom Line: While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease.Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ.Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry and Biochemistry and Biological Chemistry , Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles , Los Angeles , United States.

ABSTRACT
Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer's, Parkinson's, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer's disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers. DOI:http://dx.doi.org/10.7554/eLife.00857.001.

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Stereo view of the structural model of BAF8 with Aβ fiber.A wall-eyed stereo view of BAF8 (Figure 2D) (in cyan sticks) docked to the side of an Aβ16–21 fiber (light yellow) reveals good non-polar and polar interaction across binding interfaces. The hydrophobic binding site for the aromatic portion of BAF8 is indicated by grey mesh surfaces to highlight the good shape complementary. The polar interaction of hydrogen bonds between the charged residues Lys 16 of Aβ and the polar portion of BAF8 are indicated by black thick lines.DOI:http://dx.doi.org/10.7554/eLife.00857.009
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fig2s2: Stereo view of the structural model of BAF8 with Aβ fiber.A wall-eyed stereo view of BAF8 (Figure 2D) (in cyan sticks) docked to the side of an Aβ16–21 fiber (light yellow) reveals good non-polar and polar interaction across binding interfaces. The hydrophobic binding site for the aromatic portion of BAF8 is indicated by grey mesh surfaces to highlight the good shape complementary. The polar interaction of hydrogen bonds between the charged residues Lys 16 of Aβ and the polar portion of BAF8 are indicated by black thick lines.DOI:http://dx.doi.org/10.7554/eLife.00857.009

Mentions: (A). Outline of our procedure for structure-based screening. We prepare two sets of compounds (shown in the upper left) for screening against both types of fibers shown in the upper right. Compound Set 1 is the intersection of the ZINC Database of purchasable compounds with the Cambridge structural database (CSD) of known structures. Set 2 consists of other flat aromatic and multiple conjugated compounds found in the ZINC Database. The full description of each computational step is in ‘Materials and methods’. (B). Distribution of calculated binding energies for the compound libraries of Sets 1 and 2. Those top-ranking compounds have better predicted binding energy than orange G. Structural comparison of docked models of such compound BAF8 and orange-G is discussed in the Figure 2—figure supplement 1. Notice the starred bins which suggest that some members of Set 2, containing flat compounds, tend to be among the top scoring compounds, presumably having the tightest binding to the flat fiber surface. (C). The conformational ensemble of a compound representative shown docked onto the Aβ16–21 fiber structure. (D). A model of BAF8 docked onto an NMR-derived model of full-length Aβ fiber. Notice that the apolar ring structure of the compound binds to the relatively flat apolar (gray) surface of the fiber, and the polar moieties of the compound (red) form hydrogen bonds to the polar groups of the fiber (yellow). The stereo view of BAF8 model is shown in Figure 2—figure supplement 2.


Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta.

Jiang L, Liu C, Leibly D, Landau M, Zhao M, Hughes MP, Eisenberg DS - Elife (2013)

Stereo view of the structural model of BAF8 with Aβ fiber.A wall-eyed stereo view of BAF8 (Figure 2D) (in cyan sticks) docked to the side of an Aβ16–21 fiber (light yellow) reveals good non-polar and polar interaction across binding interfaces. The hydrophobic binding site for the aromatic portion of BAF8 is indicated by grey mesh surfaces to highlight the good shape complementary. The polar interaction of hydrogen bonds between the charged residues Lys 16 of Aβ and the polar portion of BAF8 are indicated by black thick lines.DOI:http://dx.doi.org/10.7554/eLife.00857.009
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713518&req=5

fig2s2: Stereo view of the structural model of BAF8 with Aβ fiber.A wall-eyed stereo view of BAF8 (Figure 2D) (in cyan sticks) docked to the side of an Aβ16–21 fiber (light yellow) reveals good non-polar and polar interaction across binding interfaces. The hydrophobic binding site for the aromatic portion of BAF8 is indicated by grey mesh surfaces to highlight the good shape complementary. The polar interaction of hydrogen bonds between the charged residues Lys 16 of Aβ and the polar portion of BAF8 are indicated by black thick lines.DOI:http://dx.doi.org/10.7554/eLife.00857.009
Mentions: (A). Outline of our procedure for structure-based screening. We prepare two sets of compounds (shown in the upper left) for screening against both types of fibers shown in the upper right. Compound Set 1 is the intersection of the ZINC Database of purchasable compounds with the Cambridge structural database (CSD) of known structures. Set 2 consists of other flat aromatic and multiple conjugated compounds found in the ZINC Database. The full description of each computational step is in ‘Materials and methods’. (B). Distribution of calculated binding energies for the compound libraries of Sets 1 and 2. Those top-ranking compounds have better predicted binding energy than orange G. Structural comparison of docked models of such compound BAF8 and orange-G is discussed in the Figure 2—figure supplement 1. Notice the starred bins which suggest that some members of Set 2, containing flat compounds, tend to be among the top scoring compounds, presumably having the tightest binding to the flat fiber surface. (C). The conformational ensemble of a compound representative shown docked onto the Aβ16–21 fiber structure. (D). A model of BAF8 docked onto an NMR-derived model of full-length Aβ fiber. Notice that the apolar ring structure of the compound binds to the relatively flat apolar (gray) surface of the fiber, and the polar moieties of the compound (red) form hydrogen bonds to the polar groups of the fiber (yellow). The stereo view of BAF8 model is shown in Figure 2—figure supplement 2.

Bottom Line: While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease.Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ.Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers.

View Article: PubMed Central - PubMed

Affiliation: Departments of Chemistry and Biochemistry and Biological Chemistry , Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles , Los Angeles , United States.

ABSTRACT
Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer's, Parkinson's, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer's disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers. DOI:http://dx.doi.org/10.7554/eLife.00857.001.

Show MeSH
Related in: MedlinePlus