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

ABSTRACT:

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 inhibito

SUBMITTER: Miletic V 

PROVIDER: S-EPMC5388339 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature