2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors

Nilov, Dmitry K.; Yashina, K. I.; Gushchina, Irina V.; Zakharenko, Alexandra L.; Sukhanova, Maria V.; Lavrik, Olga I.; Švedas, Vytas K.

doi:10.1134/s0006297918020074

Cited by 13 publications

(9 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Figurementioning

confidence: 99%

“…NRPS‐derived DKPs form a large class of natural products with diverse biological activities . Gliotoxin ( 1 ) is the best‐known member of the epipolythiodiketopiperazines (ETPs), a family of toxic DKPs produced by a variety of filamentous fungi . The biosynthesis of 1 has been extensively studied because of its significant contribution to the virulence of the devastating human pathogen, A. fumigatus and as a model system for fungal NRPS pathways.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Diketopiperazine Formation in Fungi Requires Dedicated Cyclization and Thiolation Domains

Baccile

Pfannenstiel

et al. 2019

Angew Chem Int Ed

View full text Add to dashboard Cite

Cyclization of linear dipeptidyl precursors derived from nonribosomal peptide synthetases (NRPSs) into 2,5diketopiperazines (DKPs) is ac rucial step in the biosynthesis of alarge number of bioactive natural products.However,the mechanism of DKP formation in fungi has remained unclear, despite extensive studies of their biosyntheses.H ere we show that DKP formation en route to the fungal virulence factor gliotoxin requires as eemingly extraneous couplet of condensation (C) and thiolation (T) domains in the NRPS GliP.I n vivo truncation of GliP to remove the CT couplet or just the T domain abrogated production of gliotoxina nd all other gli pathway metabolites.P oint mutation of conserved active sites in the Cand Tdomains diminished cyclization activity of GliP in vitro and abolished gliotoxin biosynthesis in vivo.V erified NRPSs of other fungal DKPs terminate with similar CT domain couplets,s uggesting ac onserved strategy for DKP biosynthesis by fungal NRPSs.

show abstract

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Diketopiperazine Formation in Fungi Requires Dedicated Cyclization and Thiolation Domains

Baccile

Pfannenstiel

et al. 2019

Angew Chem Int Ed

View full text Add to dashboard Cite

show abstract

“…Although strong suppression of PARP seems to be inherently toxic due to an important role played by these proteins in the organism, attempts are continuing to find the proper balance between efficacy of natural inhibitors and their toxicity. For example, PARP inhibitors were identified among caffeine metabolites [20,21] and 2,5-diketopiperazines from chicken essence (a food supplement in Asian countries) [22]. Recently we have shown that a natural nitrogenous base, 7-methylguanine (7-MG), inhibits PARP-1 in vitro and accelerates apoptotic death of BRCA-deficient breast cancer cells induced by cisplatin and doxorubicin [23].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine

Nilov

Maluchenko

Kurgina

et al. 2020

IJMS

View full text Add to dashboard Cite

7-Methylguanine (7-MG), a natural compound that inhibits DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), can be considered as a potential anticancer drug candidate. Here we describe a study of 7-MG inhibition mechanism using molecular dynamics, fluorescence anisotropy and single-particle Förster resonance energy transfer (spFRET) microscopy approaches to elucidate intermolecular interactions between 7-MG, PARP-1 and nucleosomal DNA. It is shown that 7-MG competes with substrate NAD+ and its binding in the PARP-1 active site is mediated by hydrogen bonds and nonpolar interactions with the Gly863, Ala898, Ser904, and Tyr907 residues. 7-MG promotes formation of the PARP-1–nucleosome complexes and suppresses DNA-dependent PARP-1 automodification. This results in nonproductive trapping of PARP-1 on nucleosomes and likely prevents the removal of genotoxic DNA lesions.

show abstract

“…Deficiencies of current scoring functions complicate ranking of docking poses and produce high “false positive” and “false negative” rates. However, the performance of virtual screening can be improved by postdocking structural filtration, allowing the selection of specifically bound ligands. − The main idea behind the structural filtration approach is that the presence of interactions characteristic for the substrate and/or known inhibitors could be taken as an effective criterion for the postdocking identification of new potent binders.…”

Section: Introductionmentioning

confidence: 99%

vsFilt: A Tool to Improve Virtual Screening by Structural Filtration of Docking Poses

Gushchina

Polenova

Suplatov

et al. 2020

J. Chem. Inf. Model.

View full text Add to dashboard Cite

The ability of ligands to form crucial interactions with a protein target, characteristic for the substrate and/or inhibitors, could be considered a structural criterion for identifying potent binders among docked compounds. Structural filtration of predicted poses improves the performance of virtual screening and helps in recovering specifically bound ligands. Here, we present vsFilta highly automated and easy-to-use Web server for postdocking structural filtration. The new tool can detect various types of interactions that are known to be involved in the molecular recognition, including hydrogen and halogen bonds, ionic interactions, hydrophobic contacts, π-stacking, and cation-π interactions. A case study for poly(ADP-ribose) polymerase 1 ligands illustrates the utility of the software. The Web server is freely available at https://biokinet.belozersky.msu.ru/vsfilt.

show abstract

2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors

Cited by 13 publications

References 44 publications

Diketopiperazine Formation in Fungi Requires Dedicated Cyclization and Thiolation Domains

Diketopiperazine Formation in Fungi Requires Dedicated Cyclization and Thiolation Domains

Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine

vsFilt: A Tool to Improve Virtual Screening by Structural Filtration of Docking Poses

Contact Info

Product

Resources

About