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Pregled bibliografske jedinice broj: 882836

In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1


Miletić, Vedran; Odorčić, Ivica; Nikolić, Patrik; Svedružić, Željko
In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1 // PLoS One, 12 (2017), 4; e0174410, 21 doi:10.1371/journal.pone.0174410 (međunarodna recenzija, članak, znanstveni)


CROSBI ID: 882836 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1

Autori
Miletić, Vedran ; Odorčić, Ivica ; Nikolić, Patrik ; Svedružić, Željko

Izvornik
PLoS One (1932-6203) 12 (2017), 4; E0174410, 21

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
mechanism-based inhibitor, DNA methyltransferase, Dnmt1, DNA methylation

Sažetak
Background We use our earlier experimental studies of the catalytic mechanism of DNA methyltransferases to prepare in silico a family of novel mechanism-based inhibitors of human Dnmt1. Highly specific inhibitors of DNA methylation can be used for analysis of human epigenome and for the creation of iPS cells. Results We describe a set of adenosyl-1-methyl-pyrimidin-2-one derivatives as novel mechanism-based inhibitors of mammalian DNA methyltransferase Dnmt1. The inhibitors have been designed to bind simultaneously in the active site and the cofactor site and thus act as transition-state analogues. Molecular dynamics studies showed that the lead compound can form between 6 to 9 binding interactions with Dnmt1. QM/MM analysis showed that the upon binding to Dnmt1 the inhibitor can form a covalent adduct with active site Cys1226 and thus act as a mechanism-based suicide-inhibitor. The inhibitor can target DNA-bond and DNA-free form of Dnmt1, however the suicide-inhibition step is more likely to happen when DNA is bound to Dnmt1. The validity of presented analysis is described in detail using 69 modifications in the lead compound structure. In total 18 of the presented 69 modifications can be used to prepare a family of highly specific inhibitors that can differentiate even between closely related enzymes such as Dnmt1 and Dnmt3a DNA methyltransferases.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Računarstvo



POVEZANOST RADA


Ustanove:
Sveučilište u Rijeci - Odjel za biotehnologiju

Profili:

Avatar Url Vedran Miletić (autor)

Avatar Url Željko Svedružić (autor)

Poveznice na cjeloviti tekst rada:

doi journals.plos.org www.ncbi.nlm.nih.gov

Citiraj ovu publikaciju:

Miletić, Vedran; Odorčić, Ivica; Nikolić, Patrik; Svedružić, Željko
In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1 // PLoS One, 12 (2017), 4; e0174410, 21 doi:10.1371/journal.pone.0174410 (međunarodna recenzija, članak, znanstveni)
Miletić, V., Odorčić, I., Nikolić, P. & Svedružić, Ž. (2017) In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1. PLoS One, 12 (4), e0174410, 21 doi:10.1371/journal.pone.0174410.
@article{article, year = {2017}, pages = {21}, DOI = {10.1371/journal.pone.0174410}, chapter = {e0174410}, keywords = {mechanism-based inhibitor, DNA methyltransferase, Dnmt1, DNA methylation}, journal = {PLoS One}, doi = {10.1371/journal.pone.0174410}, volume = {12}, number = {4}, issn = {1932-6203}, title = {In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1}, keyword = {mechanism-based inhibitor, DNA methyltransferase, Dnmt1, DNA methylation}, chapternumber = {e0174410} }
@article{article, year = {2017}, pages = {21}, DOI = {10.1371/journal.pone.0174410}, chapter = {e0174410}, keywords = {mechanism-based inhibitor, DNA methyltransferase, Dnmt1, DNA methylation}, journal = {PLoS One}, doi = {10.1371/journal.pone.0174410}, volume = {12}, number = {4}, issn = {1932-6203}, title = {In silico design of the first DNA-independent mechanism-based inhibitor of mammalian DNA methyltransferase Dnmt1}, keyword = {mechanism-based inhibitor, DNA methyltransferase, Dnmt1, DNA methylation}, chapternumber = {e0174410} }

Časopis indeksira:


  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


Uključenost u ostale bibliografske baze podataka::


  • AGRICOLA
  • MEDLINE
  • PsychINFO
  • Zoological Record
  • PubMed
  • Google Scholar
  • Scopus


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