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Epigenetic mechanisms leading to transcriptional regulation, including DNA methylation, are frequently dysregulated in diverse cancers. Interfering with aberrant DNA methylation performed by DNA cytosine methyltransferases (DNMTs) is a clinically validated approach. In particular, the selective inhibition of the de novo DNMT3A and DNMT3B enzymes, whose expression is limited to early embryogenesis, adult stem cells, and in cancers, is particularly attractive; such selectivity is likely to attenuate the dose limiting toxicity shown by current, non-selective DNMT inhibitors. We use molecular dynamics (MD) based computational analysis to study known small molecule binders of DNMT3A, then propose reversible, tight binding, and selective inhibitors that exploit the Asn |
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