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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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Alternative binding modes of BAF1 with the Aβ full-length fibers.When identifying BAFs by two steps of computational docking (Figure 2A as well as step B and C in Figure 1), most models of the second docking step (docking to full-length Aβ fiber in step (C) retained their binding modes found in the previous docking step (docking to Aβ16–21 fiber in step (B). Interestingly, docking of BAF1 onto full-length Aβ fiber not only recapitulated the initial binding mode found in previous Aβ16–21 docking step but also revealed the different binding mode with comparable binding energies. Two examples of those alternative binding modes are shown in (A and B). In both modes, BAF1 tends to use its polar (hydroxyl) group to interact with the charged residues Glu22 of Aβ and use its non-polar (aromatic) portion to pack against the hydrophobic residues Phe20 of Aβ full fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.006
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fig1s3: Alternative binding modes of BAF1 with the Aβ full-length fibers.When identifying BAFs by two steps of computational docking (Figure 2A as well as step B and C in Figure 1), most models of the second docking step (docking to full-length Aβ fiber in step (C) retained their binding modes found in the previous docking step (docking to Aβ16–21 fiber in step (B). Interestingly, docking of BAF1 onto full-length Aβ fiber not only recapitulated the initial binding mode found in previous Aβ16–21 docking step but also revealed the different binding mode with comparable binding energies. Two examples of those alternative binding modes are shown in (A and B). In both modes, BAF1 tends to use its polar (hydroxyl) group to interact with the charged residues Glu22 of Aβ and use its non-polar (aromatic) portion to pack against the hydrophobic residues Phe20 of Aβ full fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.006

Mentions: In the screening steps of computational docking (Figure 2A), a library of ∼18,000 purchasable compounds (Sets 1 and 2) was scanned computationally for structural compatibility with the pharmacophore (ligand binding site) presented by a single sheet of the Aβ16–21 steric zipper. Structural compatibility was assessed by a combination of binding energy (Meiler and Baker, 2006) and steric complementarity (Lawrence and Colman, 1993). After computational docking, the distribution of calculated binding energies suggests that, statistically the flat compounds from Set 2 fit more snugly on the flat surfaces of Aβ16–21 fibers than those with diverse shapes in Set 1 (Figure 2B). The best scoring compounds were screened further by requiring that each is also structurally compatible with the solid-state NMR-derived model of the Aβ full-length fiber structure (Petkova et al., 2006) (Figure 1C and Figure 1—figure supplement 3).


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)

Alternative binding modes of BAF1 with the Aβ full-length fibers.When identifying BAFs by two steps of computational docking (Figure 2A as well as step B and C in Figure 1), most models of the second docking step (docking to full-length Aβ fiber in step (C) retained their binding modes found in the previous docking step (docking to Aβ16–21 fiber in step (B). Interestingly, docking of BAF1 onto full-length Aβ fiber not only recapitulated the initial binding mode found in previous Aβ16–21 docking step but also revealed the different binding mode with comparable binding energies. Two examples of those alternative binding modes are shown in (A and B). In both modes, BAF1 tends to use its polar (hydroxyl) group to interact with the charged residues Glu22 of Aβ and use its non-polar (aromatic) portion to pack against the hydrophobic residues Phe20 of Aβ full fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.006
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1s3: Alternative binding modes of BAF1 with the Aβ full-length fibers.When identifying BAFs by two steps of computational docking (Figure 2A as well as step B and C in Figure 1), most models of the second docking step (docking to full-length Aβ fiber in step (C) retained their binding modes found in the previous docking step (docking to Aβ16–21 fiber in step (B). Interestingly, docking of BAF1 onto full-length Aβ fiber not only recapitulated the initial binding mode found in previous Aβ16–21 docking step but also revealed the different binding mode with comparable binding energies. Two examples of those alternative binding modes are shown in (A and B). In both modes, BAF1 tends to use its polar (hydroxyl) group to interact with the charged residues Glu22 of Aβ and use its non-polar (aromatic) portion to pack against the hydrophobic residues Phe20 of Aβ full fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.006
Mentions: In the screening steps of computational docking (Figure 2A), a library of ∼18,000 purchasable compounds (Sets 1 and 2) was scanned computationally for structural compatibility with the pharmacophore (ligand binding site) presented by a single sheet of the Aβ16–21 steric zipper. Structural compatibility was assessed by a combination of binding energy (Meiler and Baker, 2006) and steric complementarity (Lawrence and Colman, 1993). After computational docking, the distribution of calculated binding energies suggests that, statistically the flat compounds from Set 2 fit more snugly on the flat surfaces of Aβ16–21 fibers than those with diverse shapes in Set 1 (Figure 2B). The best scoring compounds were screened further by requiring that each is also structurally compatible with the solid-state NMR-derived model of the Aβ full-length fiber structure (Petkova et al., 2006) (Figure 1C and Figure 1—figure supplement 3).

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