Molecular Modeling of Inhibitors of Human DNA Methyltransferase with a Crystal Structure

Abstract

DNA methyltransferases (DNMTs) are promising epigenetic targets for the development of novel anticancer drugs and other diseases. Molecular modeling and experimental approaches are being used to identify and develop inhibitors of human DNMTs. Most of the computational efforts conducted so far with DNMT1 employ homology models of the enzyme. Recently, a crystallographic structure of the methyltransferase domain of human DNMT1 bound to unmethylated DNA was published. Following on our previous computational and experimental studies with DNMTs, we herein present molecular dynamics of the crystal structure of human DNMT1. Docking studies of established DNMT1 inhibitors with the crystal structure gave rise to a structure-based pharmacophore model that suggests key interactions of the inhibitors with the catalytic binding site. Results had a good agreement with the docking and pharmacophore models previously developed using a homology model of the catalytic domain of DNMT1. The docking protocol was able to distinguish active DNMT1 inhibitors from, for example, experimentally known inactive DNMT1 inhibitors. As part of our efforts to identify novel inhibitors of DNMT1, we conducted the experimental characterization of aurintricarboxylic acid (ATA) that in preliminary docking studies showed promising activity. ATA had a sub-micromolar inhibition (IC50 = 0.68 μM) against DNMT1. ATA was also evaluated for Dnmt3a inhibition showing an IC50 = 1.4 μM. This chapter illustrates the synergy from integrating molecular modeling and experimental methods for further advance the discovery of novel candidates for epigenetic therapies.

Aptamer Displacement Screen for Flaviviral RNA Methyltransferase Inhibitors

“…Results, shown in Figure 3, indicate that ATA disrupted the binding of FL-dT10 to YFV MTase with an EC 50 = 1.54 ± 0.16 µM, which is close to the IC 50 for ATA inhibition of human DNA MTases DNMT1, 0.68 µM, and DNMT3a, 1.4 µM. 32 In addition, the IC 50 for ATA inhibition of short capped RNA 2′-O methylation was 2.3 ± 0.3 µM for DENV MTase and 4.2 ± 0.2 µM for WNV MTase. 20 We next determined whether YFV MTase-vRNA bound complexes are also sensitive to the disruptive effects of ATA.…”

Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme Expression and Activity

“…Following on from the molecular modeling approach of Yoo et al [37], we carried out an implemented molecular modeling approach which consisted of a refined crystal structure of the DNMT1 catalytic domain (residues 1139-1600), IFD, and nanosecond-scale MD to study the interactions between DNMT1 and Ind. The IFD protocol allows overcoming the limitation of crystallographic structure, in which the catalytic loop is in an inactive state.…”

Epigenetic Therapy of Cancer

“…Recently, molecular dynamics of the crystal structure of human DNMT1 and docking studies have allowed the establishment of a pharmacophore model. 35 MG-98 is an antisense oligonucleotide of human DNMT1 that prevents the translation of the DNMT1 gene into the corresponding mRNA. It has reached phase II clinical studies.…”