Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor

Bach, Anders; Pedersen, Thomas B.; Strømgaard, Kristian

doi:10.1039/c5md00445d

Cited by 9 publications

(6 citation statements)

References 40 publications

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“…13−20 In recent years, the number of reports of such molecules has been growing exponentially, leading to the introduction of new therapeutic targets. Among others, triazole-based pseudopeptides are currently being studied as promising molecules in treatments against tumors (e.g., Smac mimetics, 21,22 cryptophycin-52 analogues 23 ), and neurodegenerative diseases, 24,25 as well as in tumor tracing and targeting, 26,27 mitochondrial delivery systems, 28 and as analogues of various biologically active molecules. 29,30 The growing popularity of triazole-based peptidomimetics and their constantly broadening range of applicability results in a demand for precise and elaborate theoretical research that would allow for evaluating their conformational preferences as well as to examine the physiochemical properties of this class of molecules.…”

Section: Introductionmentioning

confidence: 99%

Amber-Compatible Parametrization Procedure for Peptide-like Compounds: Application to 1,4- and 1,5-Substituted Triazole-Based Peptidomimetics

Marion

Góra

Kracker

et al. 2017

J. Chem. Inf. Model.

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Peptidomimetics are molecules of particular interest in the context of drug design and development. They are proteolytically and metabolically more stable than their natural peptide counterparts but still offer high specificity toward their biological targets. In recent years, 1,4- and 1,5-disubstituted 1,2,3-triazole-based peptidomimetics have emerged as promising lead compounds for the design of various inhibitory and tumor-targeting molecules as well as for the synthesis of peptide analogues. The growing popularity of triazole-based peptidomimetics and a constantly broadening range of their application generated a demand for elaborate theoretical investigations by classical molecular dynamics simulations and molecular docking. Despite this rising interest, accurate and coherent force field parameters for triazole-based peptidomimetics are still lacking. Here, we report the first complete set of parameters dedicated to this group of compounds, named TZLff. This parametrization is compatible with the latest version of the AMBER force field (ff14SB) and can be readily applied for the modeling of pure triazole-based peptidomimetics as well as natural peptide sequences containing one or more triazole-based modifications in their backbone. The parameters were optimized to reproduce HF/6-31G* electrostatic potentials as well as MP2/cc-pVTZ equilibrium Hessian matrices and conformational potential energy surfaces through the use of a genetic algorithm-based search and least-squares fitting. Following the standards of AMBER, we introduce residue building units, thus allowing the user to define any given sequence of triazole-based peptidomimetics. Validation of the parameter set against ab initio- and NMR-based reference systems shows that we obtain fairly accurate results, which properly capture the conformational features of triazole-based peptidomimetics. The successful and efficient parametrization strategy developed in this work is general enough to be applied in a straightforward manner for parametrization of other peptidomimetics and, potentially, any polymeric assemblies.

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Section: Introductionmentioning

confidence: 99%

Amber-Compatible Parametrization Procedure for Peptide-like Compounds: Application to 1,4- and 1,5-Substituted Triazole-Based Peptidomimetics

Marion

Góra

Kracker

et al. 2017

J. Chem. Inf. Model.

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“…PDZ inhibitors, which were able to disrupt the PSD-95-PDZ2/GluN2B PPI, were discovered using a rational "click chemistry" strategy [29]. The aim was to mimic the TAV/SAV tripeptide PSD-95 ligand using triazole-containing compounds that were easily synthesized from reactive azide and alkyne moieties.…”

Section: Pdz Domains As Potential Drug Targetsmentioning

confidence: 99%

Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains

Hoffer

Roché

Morelli

2021

Methods in Molecular Biology

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PDZ domains, which belong to protein-protein interaction networks, are critical for regulating important biological processes such as scaffolding, trafficking and signaling cascades. Interfering with PDZ-mediated interactions could affect these numerous biological processes. Thus, PDZ domains have emerged as promising targets to decipher biological phenomena and potentially treat cancer and neurological diseases. In this minireview, we focus on the discovery and design of small molecule inhibitors to modulate PDZ domains. These compounds interfere with endogenous protein partners from the PDZ domain by binding at the proteinprotein interface. While peptides or peptidomimetic ligands were described to modulate PDZ domains, the focus of this review is on small organic compounds.

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“…However, development of small‐molecule PDZ domain inhibitors has proven to be very difficult [8] . Except for Biogen's tripeptide‐like nanomolar PICK1 PDZ domain inhibitors, [9] potent (<1 μM) small molecules are lacking for the ∼260 human PDZ domains, including those of PSD‐95 [10] . A better understanding of PDZ domains and their ligand‐binding capabilities could open up for new chemical probes and drug candidates towards a plethora of biological relevant proteins.…”

Section: Figurementioning

confidence: 99%

Identification of Novel Fragments Binding to the PDZ1‐2 Domain of PSD‐95

Zang

Solbak

et al. 2020

ChemMedChem

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Inhibition of PSD‐95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide‐based compounds that target the PDZ domains of PSD‐95. In contrast, developing potent and drug‐like small molecules against the PSD‐95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD‐95 PDZ1‐2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter‐test, and found four promising fragments. Three ligand efficient fragments were shown by 1H,15N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1‐2, and one of them underwent structure‐activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1‐2 of PSD‐95 and disclose novel fragments that can serve as starting points for optimization towards small‐molecule PDZ domain inhibitors.

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Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor

Abstract: A novel PSD-95 PDZ2 peptidomimetic has been discovered by designing azide and alkyne amino acid analogues and click chemistry.

Cited by 9 publications

References 40 publications

Amber-Compatible Parametrization Procedure for Peptide-like Compounds: Application to 1,4- and 1,5-Substituted Triazole-Based Peptidomimetics

Amber-Compatible Parametrization Procedure for Peptide-like Compounds: Application to 1,4- and 1,5-Substituted Triazole-Based Peptidomimetics

Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains

Identification of Novel Fragments Binding to the PDZ1‐2 Domain of PSD‐95

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