Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions

Fujii, Naoaki; Haresco, Jose J.; Novak, Kathleen A. P.; Gage, Robert M.; Pedemonte, Nicoletta; Stokoe, David; Kuntz, Irwin D.; Guy, R. Kiplin

doi:10.1016/j.bmcl.2006.10.006

Cited by 28 publications

(27 citation statements)

References 13 publications

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“…By using a newly developed reversible inhibitor, a reduction of CFTR activation by CPT-cAMP in bronchial airway cells was achieved (51). In line with our finding that CFTR interaction with NHERF-1 is important for its full activation in native epithelium, this suggests that a novel class of anti-diarrheal drugs could potentially be developed that targets interactions of NHERF-1 with its binding partners.…”

Section: Discussionsupporting

confidence: 59%

Cystic Fibrosis Transmembrane Conductance Regulator Activation Is Reduced in the Small Intestine of Na+/H+ Exchanger 3 Regulatory Factor 1 (NHERF-1)- but Not NHERF-2-deficient Mice

Broere

Hillesheim

Tuo

et al. 2007

Journal of Biological Chemistry

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Binding of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel to the Na؉ /H ؉ exchanger 3 regulatory factor 1 (NHERF-1) and NHERF-2 scaffolding proteins has been shown to affect its localization and activation. We have for the first time studied the physiological role of these proteins in CFTR regulation in native tissue by determining CFTRdependent chloride current in NHERF-1-and NHERF-2-deficient mice. The cAMP-and cGMP-activated chloride current and the basal chloride current in basolaterally permeabilized jejunum were reduced by ϳ30% in NHERF-1-deficient mice but not in NHERF-2-deficient mice. The duodenal bicarbonate secretion was affected in a similar way, whereas no significant differences in CFTR activity were observed in ileum. CFTR abundance as determined by Western blotting was unaltered in jejunal epithelial cells and brush border membranes of NHERF-1 and NHERF-2 mutant mice. However, semi-quantitative detection of CFTR by confocal microscopy showed that the level of apically localized CFTR in jejunal crypts was reduced by ϳ35% in NHERF-1-deficient and NHERF-1/2 double deficient mice but not in NHERF-2 null mice. Together our results indicate that NHERF-1 is required for full activation of CFTR in murine duodenal and jejunal mucosa and that NHERF-1 affects the local distribution of CFTR in or near the plasma membrane.These studies provide the first evidence in native intestinal epithelium that NHERF-1 but not NHERF-2 is involved in the formation of CFTR-containing functional complexes that serve to position CFTR in the crypt apical membrane and/or to optimize its function as a cAMP-and cGMP-regulated anion channel.

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Section: Discussionsupporting

confidence: 59%

Cystic Fibrosis Transmembrane Conductance Regulator Activation Is Reduced in the Small Intestine of Na+/H+ Exchanger 3 Regulatory Factor 1 (NHERF-1)- but Not NHERF-2-deficient Mice

Broere

Hillesheim

Tuo

et al. 2007

Journal of Biological Chemistry

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“…56 and 58. Compound number 56 is shown to inhibit PDZ1 domain of NHERF1 [51], while the compound number 58 inhibits PDZ3 domain of PSD-95 protein [52]. Remaining 11 molecules with known K i values in cluster two, have been experimentally characterized to inhibit Dishevelled PDZ domain [24], [53], [54].…”

Section: Resultsmentioning

confidence: 99%

An In Silico Analysis of the Binding Modes and Binding Affinities of Small Molecule Modulators of PDZ-Peptide Interactions

Tiwari

Mohanty

2013

PLoS ONE

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Inhibitors of PDZ-peptide interactions have important implications in a variety of biological processes including treatment of cancer and Parkinson’s disease. Even though experimental studies have reported characterization of peptidomimetic inhibitors of PDZ-peptide interactions, the binding modes for most of them have not been characterized by structural studies. In this study we have attempted to understand the structural basis of the small molecule-PDZ interactions by in silico analysis of the binding modes and binding affinities of a set of 38 small molecules with known Ki or Kd values for PDZ2 and PDZ3 domains of PSD-95 protein. These two PDZ domains show differential selectivity for these compounds despite having a high degree of sequence similarity and almost identical peptide binding pockets. Optimum binding modes for these ligands for PDZ2 and PDZ3 domains were identified by using a novel combination of semi-flexible docking and explicit solvent molecular dynamics (MD) simulations. Analysis of the binding modes revealed most of the peptidomimectic ligands which had high Ki or Kd moved away from the peptide binding pocket, while ligands with high binding affinities remained in the peptide binding pocket. The differential specificities of the PDZ2 and PDZ3 domains primarily arise from differences in the conformation of the loop connecting βB and βC strands, because this loop interacts with the N-terminal chemical moieties of the ligands. We have also computed the MM/PBSA binding free energy values for these 38 compounds with both the PDZ domains from multiple 5 ns MD trajectories on each complex i.e. a total of 228 MD trajectories of 5 ns length each. Interestingly, computational binding free energies show good agreement with experimental binding free energies with a correlation coefficient of approximately 0.6. Thus our study demonstrates that combined use of docking and MD simulations can help in identification of potent inhibitors of PDZ-peptide complexes.

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“…Accordingly, the binding pocket of PDZ domains is shallow and relatively nondescript with very few points of interaction, 29,37 and therefore, the interactions of PDZ domains with their targets are typically difficult to inhibit. 39,40 …”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibition of the Na⁺/H⁺ Exchange Regulatory Factor 1 and Parathyroid Hormone 1 Receptor Interaction

et al. 2014

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We have identified a series of small molecules that bind to the canonical peptide binding groove of the PDZ1 domain of NHERF1 and effectively compete with the association of the C-terminus of the parathyroid hormone 1 receptor (PTH1R). Employing nuclear magnetic resonance and molecular modeling, we characterize the mode of binding that involves the GYGF loop important for the association of the C-terminus of PTH1R. We demonstrate that the common core of the small molecules binds to the PDZ1 domain of NHERF1 and displaces a 15N-labeled peptide corresponding to the C-terminus of PTH1R. The small size (molecular weight of 192) of this core scaffold makes it an excellent candidate for further elaboration in the development of an inhibitor for this important protein–protein interaction.

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Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions

Cited by 28 publications

References 13 publications

Cystic Fibrosis Transmembrane Conductance Regulator Activation Is Reduced in the Small Intestine of Na+/H+ Exchanger 3 Regulatory Factor 1 (NHERF-1)- but Not NHERF-2-deficient Mice

Cystic Fibrosis Transmembrane Conductance Regulator Activation Is Reduced in the Small Intestine of Na+/H+ Exchanger 3 Regulatory Factor 1 (NHERF-1)- but Not NHERF-2-deficient Mice

An In Silico Analysis of the Binding Modes and Binding Affinities of Small Molecule Modulators of PDZ-Peptide Interactions

Small Molecule Inhibition of the Na⁺/H⁺ Exchange Regulatory Factor 1 and Parathyroid Hormone 1 Receptor Interaction

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Rational design of a nonpeptide general chemical scaffold for reversible inhibition of PDZ domain interactions

Cited by 28 publications

References 13 publications

Cystic Fibrosis Transmembrane Conductance Regulator Activation Is Reduced in the Small Intestine of Na+/H+ Exchanger 3 Regulatory Factor 1 (NHERF-1)- but Not NHERF-2-deficient Mice

Cystic Fibrosis Transmembrane Conductance Regulator Activation Is Reduced in the Small Intestine of Na+/H+ Exchanger 3 Regulatory Factor 1 (NHERF-1)- but Not NHERF-2-deficient Mice

An In Silico Analysis of the Binding Modes and Binding Affinities of Small Molecule Modulators of PDZ-Peptide Interactions

Small Molecule Inhibition of the Na+/H+ Exchange Regulatory Factor 1 and Parathyroid Hormone 1 Receptor Interaction

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Small Molecule Inhibition of the Na⁺/H⁺ Exchange Regulatory Factor 1 and Parathyroid Hormone 1 Receptor Interaction