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. 2020 Dec 27;14(1):17.
doi: 10.3390/ph14010017.

Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

K Eurídice Juárez-Mercado  1 , Fernando D Prieto-Martínez  1 , Norberto Sánchez-Cruz  1 , Andrea Peña-Castillo  1 , Diego Prada-Gracia  2 , José L Medina-Franco  1
Affiliations

Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

K Eurídice Juárez-Mercado et al. Pharmaceuticals (Basel). .

Abstract

Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores.

Keywords: chemoinformatics; dietary component; enzyme inhibition; epi-informatics; epigenetics; focused library; multitarget epigenetic agent; natural products.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of representative DNA methyltransferase (DNMT) inhibitors and other compounds with associated hypomethylating properties from different sources. (A) approved drugs; (B) drug repurposing; (C) natural products and dietary components; (D) small molecules: synthetic compounds.
Figure 2
Figure 2
Chemical structures of 10 compounds from different sources experimentally tested. Compounds are grouped by their source: (A) approved drugs; (B) dietary source (natural product); (C) inhibitor of the viral NS5 RNA methyltransferase; (D) DNMT-focused library.
Figure 3
Figure 3
Binding poses predicted with the Molecular with Molecular Operating Environment v.2018 of the five active compounds with the catalytic domain of DNA methyltransferase 1.
Figure 4
Figure 4
Correlation between the experimental pIC50 of the five compounds evaluated in biochemical inhibition assays of DNMT1 with (A) the docking scores calculated with MOE, and (B) the ECIF6::LD-GBT scores.
Figure 5
Figure 5
Free energy landscape of the glyburide–DNMT1 complex along the slowest independent components (A); microstate distribution as obtained with the Perron Cluster Analysis PCCA+ sampling (B); contact frequency obtained from the discretized microstates (C).
See this image and copyright information in PMC

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