Title:Do Anticancer Medicinal Compounds have DNMT1 Regulating Activity: An In silico Investigation
Volume: 21
Issue: 16
Author(s): Fahad Hassan Shah*Song Ja Kim*
Affiliation:
- Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, 32588, Republic
of Korea
- Department of Biological Sciences, College of Natural Sciences, Kongju National University, Gongju, 32588, Republic
of Korea
Keywords:
Medicinal compounds, DNA methyltransferases, molecular docking, in silico gene expression, DNMT1, ADMET properties.
Abstract:
Background: DNA methyltransferases (DNMTs) are a group of epigenetic enzymes
implicated in regulating gene expression in actively dividing cells. Among these enzymes,
DNMT1 plays a leading role in causing increased DNA methylation of tumor suppressors and
other genes in cancer cells. This methylation event disrupts the cell cycle regulating genes, allowing
an uninterrupted proliferation of cancer cells, and stimulating the inhibition of the degradation
of proteins and aberrant transcription activation. Cytosine analog drugs have been shown
to reduce DNA methylation but provoke the expression of other prometastatic genes. On the
other hand, medicinal compounds act similarly to cytosine analogs by reducing the expression
and activity of DNMT1, as reported in some in vitro cancer studies. However, it remains a mystery
what those promising medicinal compounds are that show such activity.
Objectives: The objective of this study was to screen medicinal compounds that reduce the expression
and interact with the active site residues of DNMT1.
Methods: To analyze medicinal compounds against DNMT1, two in silico tools were employed:
DIGEP-pred and IGEMDOCK to discover and identify 98 lead medicinal compounds having
anticancer potential, capable of regulating DNMT1 expression and activity.
Results: Our results have identified twenty (20) medicinal compounds that reduced the expression
of DNMT1 up to 50-77% as compared to the standard cytosine analog (91.5%). These compounds
have also interacted with the reported active site residues of DNMT1, as predicted by
IGEMDOCK. These compounds have adequate druglikeness, toxicity, and pharmacokinetic
properties as described by Protox-II and ADMET lab 2.0.
Conclusion: Thus, our study provides an initial report of those medicinal compounds that have
DNMT1 targeting ability and have a relatively safer pharmacokinetic and toxicity profile.
