Molecular modeling of inhibitors of human DNa methyltransferase with a crystal structure: Discovery of a novel dnmt1 inhibitor

Jakyung Yoo, Joo Hee Kim, Keith D Robertson, José L. Medina-Franco

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 submicromolar inhibition (IC 50 = 0.68 μM) against DNMT1. ATA was also evaluated for Dnmt3a inhibition showing an IC 50 = 1.4 μM. This chapter illustrates the synergy from integrating molecular modeling and experimental methods to further advance the discovery of novel candidates for epigenetic therapies.

Original languageEnglish (US)
Pages (from-to)219-247
Number of pages29
JournalAdvances in Protein Chemistry and Structural Biology
Volume87
DOIs
StatePublished - 2012
Externally publishedYes

Fingerprint

Molecular modeling
Aurintricarboxylic Acid
Methyltransferases
Crystal structure
DNA
Epigenomics
Catalytic Domain
Molecular Dynamics Simulation
Molecular dynamics
Binding Sites
Enzymes
Pharmaceutical Preparations
Therapeutics

Keywords

  • Cancer
  • DNMT
  • Docking
  • Drug discovery
  • Epigenetics
  • Molecular dynamics
  • Pharmacophore modeling

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology

Cite this

Molecular modeling of inhibitors of human DNa methyltransferase with a crystal structure : Discovery of a novel dnmt1 inhibitor. / Yoo, Jakyung; Kim, Joo Hee; Robertson, Keith D; Medina-Franco, José L.

In: Advances in Protein Chemistry and Structural Biology, Vol. 87, 2012, p. 219-247.

Research output: Contribution to journalArticle

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