Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase

Shaw, Scott A.; Vokits, Benjamin; Dilger, Andrew K.; Viet, Andrew Q.; Clark, C. G.; Abell, Lynn M.; Locke, Gregory; Duke, Gerald J.; Kopcho, Lisa M.; Dongre, Ashok; Gao, Ji; Krishnakumar, Arathi; Jusuf, Sutjano; Khan, Javed; Spronk, Steven A.; Basso, Michael; Zhao, Lei; Cantor, Glenn H.; Onorato, Joelle M.; Wexler, Ruth R.; Duclos, Franck; Kick, Ellen K.

doi:10.1016/j.bmc.2020.115723

Cited by 20 publications

(16 citation statements)

References 29 publications

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“…Likewise, similar to the reference peptides, each CS peptide could interact with 4-5 of the seven key residues in the active site of MPO. These key residues contributed to the stability of the interaction between 7-benzyl-1H-[1,2,3]triazolo[4,5-b]pyridin-5-amine, the bound inhibitor in the MPO crystal, and the active site of MPO [25]. As observed in the two reference peptides, all the five CS peptides could bind directly to the heme moiety of MPO (Table 7).…”

Section: Molecular Docking Of Peptides On Mpomentioning

confidence: 76%

“…The X-ray crystal structures of murine Keap1 in complex with inhibitor RA839 (PDB code: 5CGJ) [7], human MPO bound to inhibitor 7-benzyl-1H- [1,2,3]triazolo [4,5-b]pyridin-5-amine (PDB code: 6WYD) [25], and bovine XO complexed with quercetin (PDB code: 3NVY) [26] were downloaded from the RCSB Protein Data Bank (https://www.rcsb. org) [27,28] (access date: 19 June 2021).…”

Section: Docking-based Screening Of Potential Inhibitors Of Keap1 Mpo and Xomentioning

confidence: 99%

“…a Number in brackets indicates the number of interactions. Residues in bold are key residues (Gln91, His95, Phe99, Arg239, His336, Phe366, and Phe407) in the active site of MPO[25].…”

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confidence: 99%

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Purification, Identification and Characterization of Antioxidant Peptides from Corn Silk Tryptic Hydrolysate: An Integrated In Vitro-In Silico Approach

et al. 2021

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Corn silk (CS) is an agro-by-product from corn cultivation. It is used in folk medicines in some countries, besides being commercialized as health-promoting supplements and beverages. Unlike CS-derived natural products, their bioactive peptides, particularly antioxidant peptides, are understudied. This study aimed to purify, identify and characterize antioxidant peptides from trypsin-hydrolyzed CS proteins. Purification was accomplished by membrane ultrafiltration, gel filtration chromatography, and strong-cation-exchange solid-phase extraction, guided by 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical cation (ABTS•+) scavenging, hydrogen peroxide scavenging, and lipid peroxidation inhibition assays. De novo sequencing identified 29 peptides (6–14 residues; 633–1518 Da). The peptides consisted of 33–86% hydrophobic and 10–67% basic residues. Molecular docking found MCFHHHFHK, VHFNKGKKR, and PVVWAAKR having the strongest affinity (−4.7 to −4.8 kcal/mol) to ABTS•+, via hydrogen bonds and hydrophobic interactions. Potential cellular mechanisms of the peptides were supported by their interactions with modulators of intracellular oxidant status: Kelch-like ECH-associated protein 1, myeloperoxidase, and xanthine oxidase. NDGPSR (Asn-Asp-Gly-Pro-Ser-Arg), the most promising peptide, showed stable binding to all three cellular targets, besides exhibiting low toxicity, low allergenicity, and cell-penetrating potential. Overall, CS peptides have potential application as natural antioxidant additives and functional food ingredients.

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Section: Molecular Docking Of Peptides On Mpomentioning

confidence: 76%

Section: Docking-based Screening Of Potential Inhibitors Of Keap1 Mpo and Xomentioning

confidence: 99%

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Purification, Identification and Characterization of Antioxidant Peptides from Corn Silk Tryptic Hydrolysate: An Integrated In Vitro-In Silico Approach

et al. 2021

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“…LYSPH showed the strongest binding to MPO, whereas PSYLNTPLL the weakest ( Table 2 ), similar to our observations when the five peptides were docked to Keap1 ( Table 1 ). None of the peptides showed better binding affinity to MPO than did 7-benzyl-1H-[1–3]triazolo[4,5-b]pyridin-5-amine (7GD)(−7.1 kcal/mol) (data not shown), a co-crystalized inhibitor of MPO [ 41 ]. However, all five peptides could form hydrophobic interactions with one of the catalytic residues (Arg239) of MPO.…”

Section: Resultsmentioning

confidence: 99%

“…Supporting this possibility is the finding that two experimentally-validated anti-MPO peptides (TDY and FAPQY) could also bind to Arg239 and the heme group of MPO [ 43 ]. Analysis of intermolecular interactions revealed that LYSPH could form hydrophobic interactions with Phe99, Thr238, Arg239, Glu242, Phe366, Phe407, and Hec606 of MPO ( Table 2 ), resembling to the binding pattern of 7GD [ 41 ]. Hence, LYSPH is the most promising MPO inhibitor among the five peptides as it showed the best binding affinity to MPO and could interact with MPO similarly as 7GD.…”

Section: Resultsmentioning

confidence: 99%

Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach

et al. 2021

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Some seed-derived antioxidant peptides are known to regulate cellular modulators of ROS production, including those proposed to be promising targets of anticancer therapy. Nevertheless, research in this direction is relatively slow owing to the inevitable time-consuming nature of wet-lab experimentations. To help expedite such explorations, we performed structure-based virtual screening on seed-derived antioxidant peptides in the literature for anticancer potential. The ability of the peptides to interact with myeloperoxidase, xanthine oxidase, Keap1, and p47phox was examined. We generated a virtual library of 677 peptides based on a database and literature search. Screening for anticancer potential, non-toxicity, non-allergenicity, non-hemolyticity narrowed down the collection to five candidates. Molecular docking found LYSPH as the most promising in targeting myeloperoxidase, xanthine oxidase, and Keap1, whereas PSYLNTPLL was the best candidate to bind stably to key residues in p47phox. Stability of the four peptide-target complexes was supported by molecular dynamics simulation. LYSPH and PSYLNTPLL were predicted to have cell- and blood-brain barrier penetrating potential, although intolerant to gastrointestinal digestion. Computational alanine scanning found tyrosine residues in both peptides as crucial to stable binding to the targets. Overall, LYSPH and PSYLNTPLL are two potential anticancer peptides that deserve deeper exploration in future.

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Inhibition of Myeloperoxidase

Soubhye

Furtmüller

Dufrasne

et al. 2020

Reactive Oxygen Species

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Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase

Cited by 20 publications

References 29 publications

Purification, Identification and Characterization of Antioxidant Peptides from Corn Silk Tryptic Hydrolysate: An Integrated In Vitro-In Silico Approach

Purification, Identification and Characterization of Antioxidant Peptides from Corn Silk Tryptic Hydrolysate: An Integrated In Vitro-In Silico Approach

Computational Screening for the Anticancer Potential of Seed-Derived Antioxidant Peptides: A Cheminformatic Approach

Inhibition of Myeloperoxidase

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