Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains

Boucherle, Benjamin; Vogrig, Alexandre; Deokar, Hemantkumar; Bouzidi, Naoual; Ripoche, Isabelle; Thomas, Isabelle; Marin, Philippe; Ducki, Sylvie

doi:10.1016/j.bmc.2011.05.036

Cited by 7 publications

(9 citation statements)

References 42 publications

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“…The binding of the inhibitors 38, 48 and 49 to the PDZ1 domain of PSD-95 protein was demonstrated by NMR spectrometry [49]. The compound number 50 was predicted initially by docking studies and subsequently the prediction was confirmed by biochemical studies [50]. Out of the 13 molecules in the second cluster (cyan colored), K i or K d values were not known for two molecules i.e.…”

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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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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“…Many research groups are focusing on PDZ domains as the target platform of protein–protein interaction inhibitors [31,32,40,41]. Simultaneously, based on the more physiological interest, genome-wide proteomics studies on all mammalian PDZ domains with their targets were reported [42], indicating the physiological and pharmacological importance of PDZ proteins in the human body.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, PDZ domains have been considered attractive candidates for drug discovery [29]. Recently, some non-peptide inhibitors of PDZ domains have emerged [30,31,32]. Thus, we focused on the predicted protein–ligand sets containing PDZ domains in the SAHG database.…”

Section: Introductionmentioning

confidence: 99%

Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening

et al. 2013

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Abstract:In silico approaches have become indispensable for drug discovery as well as drug repositioning and adverse effect prediction. We have developed the eF-seek program to predict protein-ligand interactions based on the surface structure of proteins using a clique search algorithm. We have also developed a special protein structure prediction pipeline and accumulated predicted 3D models in the Structural Atlas of the Human Genome (SAHG) database. Using this database, genome-wide prediction of non-peptide ligands for proteins in the human genome was performed, and a subset of predicted interactions including 14 PDZ domains was then confirmed by NMR titration. Surprisingly, diclofenac, a non-steroidal anti-inflammatory drug, was found to be a non-peptide PDZ OPEN ACCESSMolecules 2013, 18 9568 domain ligand, which bound to 5 of 15 tested PDZ domains. The critical residues for the PDZ-diclofenac interaction were also determined. Pharmacological implications of the accidental PDZ-diclofenac interaction are further discussed.

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“…The interacting surface for each position is referred to as a site or socket, for example, S 0 interacts with residue P 0 , S -1 with P -1 , etc. (Amacher et al, 2014;Boucherle et al, 2011;Madsen et al, 2005). To date, inhibitor development has followed a general pipeline, as summarized in Fig.…”

Section: Therapeutically Targeting Pdz Domains To Combat Human Diseasementioning

confidence: 99%

Specificity in PDZ-peptide interaction networks: Computational analysis and review

Amacher

Brooks

Hampton

et al. 2020

Journal of Structural Biology: X

117

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Globular PDZ domains typically serve as protein-protein interaction modules that regulate a wide variety of cellular functions via recognition of short linear motifs (SLiMs). Often, PDZ mediated-interactions are essential components of macromolecular complexes, and disruption affects the entire scaffold. Due to their roles as linchpins in trafficking and signaling pathways, PDZ domains are attractive targets: both for controlling viral pathogens, which bind PDZ domains and hijack cellular machinery, as well as for developing therapies to combat human disease. However, successful therapeutic interventions that avoid off-target effects are a challenge, because each PDZ domain interacts with a number of cellular targets, and specific binding preferences can be difficult to decipher. Over twenty-five years of research has produced a wealth of data on the stereochemical preferences of individual PDZ proteins and their binding partners. Currently the field lacks a central repository for this information.Here, we provide this important resource and provide a manually curated, comprehensive list of the 271 human PDZ domains. We use individual domain, as well as recent genomic and proteomic, data in order to gain a holistic view of PDZ domains and interaction networks, arguing this knowledge is critical to optimize targeting selectivity and to benefit human health.Amacher et. al.

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Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains

Cited by 7 publications

References 42 publications

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

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

Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening

Specificity in PDZ-peptide interaction networks: Computational analysis and review

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