The Experts below are selected from a list of 213618 Experts worldwide ranked by ideXlab platform
Dale L Boger - One of the best experts on this subject based on the ideXlab platform.
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comprehensive peptidomimetic libraries Targeting Protein Protein interactions
Accounts of Chemical Research, 2012Co-Authors: Landon R Whitby, Dale L BogerAbstract:Transient Protein–Protein interactions (PPIs) are essential components in cellular signaling pathways as well as in important processes such as viral infection, replication, and immune suppression. The unknown or uncharacterized PPIs involved in such interaction networks often represent compelling therapeutic targets for drug discovery. To date, however, the main strategies for discovery of small molecule modulators of PPIs are typically limited to structurally characterized targets.Recent developments in molecular scaffolds that mimic the side chain display of peptide secondary structures have yielded effective designs, but few screening libraries of such mimetics are available to interrogate PPI targets. We initiated a program to prepare a comprehensive small molecule library designed to mimic the three major recognition motifs that mediate PPIs (α-helix, β-turn, and β-strand). Three libraries would be built around templates designed to mimic each such secondary structure and substituted with all triple...
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Analysis of a geometric characterization of 10 245 β-turns in the Protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (Ki = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the...
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Ana...
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design synthesis and evaluation of an α helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small-molecule library Targeting Protein−Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid−liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the lib...
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design synthesis and evaluation of an alpha helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library Targeting Protein-Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated Protein-Protein interaction) and define the key residues and their characteristics responsible for recognition.
Landon R Whitby - One of the best experts on this subject based on the ideXlab platform.
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comprehensive peptidomimetic libraries Targeting Protein Protein interactions
Accounts of Chemical Research, 2012Co-Authors: Landon R Whitby, Dale L BogerAbstract:Transient Protein–Protein interactions (PPIs) are essential components in cellular signaling pathways as well as in important processes such as viral infection, replication, and immune suppression. The unknown or uncharacterized PPIs involved in such interaction networks often represent compelling therapeutic targets for drug discovery. To date, however, the main strategies for discovery of small molecule modulators of PPIs are typically limited to structurally characterized targets.Recent developments in molecular scaffolds that mimic the side chain display of peptide secondary structures have yielded effective designs, but few screening libraries of such mimetics are available to interrogate PPI targets. We initiated a program to prepare a comprehensive small molecule library designed to mimic the three major recognition motifs that mediate PPIs (α-helix, β-turn, and β-strand). Three libraries would be built around templates designed to mimic each such secondary structure and substituted with all triple...
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Analysis of a geometric characterization of 10 245 β-turns in the Protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (Ki = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the...
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Ana...
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design synthesis and evaluation of an α helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small-molecule library Targeting Protein−Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid−liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the lib...
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design synthesis and evaluation of an alpha helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library Targeting Protein-Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated Protein-Protein interaction) and define the key residues and their characteristics responsible for recognition.
Peter K Vogt - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Analysis of a geometric characterization of 10 245 β-turns in the Protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (Ki = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the...
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Ana...
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design synthesis and evaluation of an α helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small-molecule library Targeting Protein−Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid−liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the lib...
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design synthesis and evaluation of an alpha helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library Targeting Protein-Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated Protein-Protein interaction) and define the key residues and their characteristics responsible for recognition.
Alex Shaginian - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and evaluation of an α helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small-molecule library Targeting Protein−Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid−liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the lib...
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design synthesis and evaluation of an alpha helix mimetic library Targeting Protein Protein interactions
Journal of the American Chemical Society, 2009Co-Authors: Alex Shaginian, Landon R Whitby, Sukwon Hong, Inkyu Hwang, Bilal Farooqi, Mark Searcey, Jiandong Chen, Peter K Vogt, Dale L BogerAbstract:The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library Targeting Protein-Protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated Protein-Protein interaction) and define the key residues and their characteristics responsible for recognition.
Bryan L Roth - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Analysis of a geometric characterization of 10 245 β-turns in the Protein data bank (PDB) suggested that trans-pyrrolidine-3,4-dicarboxamide could serve as an effective and synthetically accessible library template. This was confirmed by initially screening select compounds against a series of peptide-activated GPCRs that recognize a β-turn structure in their endogenous ligands. This validation study was highlighted by identification of both nonbasic and basic small molecules with high affinities (Ki = 390 and 23 nM, respectively) for the κ-opioid receptor (KOR). Consistent with the screening capabilities of collaborators and following the design validation, the complete library was assembled as 210 mixtures of 20 compounds, providing a total of 4200 compounds designed to mimic all possible permutations of 3 of the...
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design synthesis and validation of a β turn mimetic library Targeting Protein Protein and peptide receptor interactions
Journal of the American Chemical Society, 2011Co-Authors: Landon R Whitby, Peter K Vogt, Yoshio Ando, Vincent Setola, Bryan L Roth, Dale L BogerAbstract:The design and synthesis of a β-turn mimetic library as a key component of a small-molecule library Targeting the major recognition motifs involved in Protein–Protein interactions is described. Ana...
