Journal of Computer-Aided Molecular Design

, Volume 25, Issue 6, pp 555–567 | Cite as

Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase

  • Jakyung Yoo
  • José L. Medina-FrancoEmail author


DNA methyltransferase 1 (DNMT1) is an emerging epigenetic target for the treatment of cancer and other diseases. To date, several inhibitors from different structural classes have been published. In this work, we report a comprehensive molecular modeling study of 14 established DNTM1 inhibitors with a herein developed homology model of the catalytic domain of human DNTM1. The geometry of the homology model was in agreement with the proposed mechanism of DNA methylation. Docking results revealed that all inhibitors studied in this work have hydrogen bond interactions with a glutamic acid and arginine residues that play a central role in the mechanism of cytosine DNA methylation. The binding models of compounds such as curcumin and parthenolide suggest that these natural products are covalent blockers of the catalytic site. A pharmacophore model was also developed for all DNMT1 inhibitors considered in this work using the most favorable binding conformations and energetic terms of the docked poses. To the best of our knowledge, this is the first pharmacophore model proposed for compounds with inhibitory activity of DNMT1. The results presented in this work represent a conceptual advance for understanding the protein–ligand interactions and mechanism of action of DNMT1 inhibitors. The insights obtained in this work can be used for the structure-based design and virtual screening for novel inhibitors targeting DNMT1.


Cancer DNMT Docking Epigenetics Homology model Pharmacophore 



Authors thank Dr. Fabian López-Vallejo and Dr. Thomas Caulfield for helpful discussions. We also thank Karen Gottwald for proofreading the manuscript. This work was supported by the Menopause & Women’s Health Research Center and the State of Florida, Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development.

Supplementary material

10822_2011_9441_MOESM1_ESM.doc (1.1 mb)
Supplementary material 1 (DOC 1171 kb)


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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Torrey Pines Institute for Molecular StudiesPort St. LucieUSA

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