Anticancer Drug Discovery Targeting DNA Hypermethylation

Yu, Neng-Wei; Wang, Ming-Rong

doi:10.2174/092986708784567653

Cited by 41 publications

(26 citation statements)

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“…Procaine and procainamide are approved drugs as local anesthetic and for the treatment of cardiac arrhythmias [17,48], respectively. Figure 5b shows the binding mode of procaine.…”

Section: Non-covalent Blockersmentioning

confidence: 99%

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

Yoo

Medina‐Franco

2011

J Comput Aided Mol Des

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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.

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“…Procaine and procainamide are approved drugs as local anesthetic and for the treatment of cardiac arrhythmias [17,48], respectively. Figure 5b shows the binding mode of procaine.…”

Section: Non-covalent Blockersmentioning

confidence: 99%

“…In this work, DNMT inhibitors are classified into four major groups mainly depending on the associated mechanism of inhibition ( Table 1): (1) Nucleoside analogues such as 5-azacytidine [14][15][16][17][18], decitabine [19][20][21][22][23], 5-fluoro-2 0 -deoxy-cytidine [24,25], and zebularine [26][27][28][29][30];…”

Section: Introductionmentioning

confidence: 99%

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

Yoo

Medina‐Franco

2011

J Comput Aided Mol Des

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“…In addition, approved drugs for other indications such as hydralazine (18,19), procaine (20,21), procainamide (22), or antibiotics such as mithramycin A (23) have also been reported to inhibit DNA methylation. Additional DNMT inhibitors are reviewed elsewhere (10,24,25).…”

Section: Introductionmentioning

confidence: 99%

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Kuck

Caulfield

Lyko

et al. 2010

Molecular Cancer Therapeutics

150

116

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Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes. Mol Cancer Ther; 9(11); 3015-23.

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“…Currently, 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine) are the only two that are approved by the US Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome. [3] However, whether their clinical efficacy in this condition results from their demethylating activities or by their intrinsic cytotoxicity remains to be fully elucidated. [4][5][6][7] Thus, specific inhibition of DNMT1 is an attractive and novel approach for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Molecular Modeling and Molecular Dynamics Studies of Hydralazine with Human DNA Methyltransferase 1

et al. 2009

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DNA methyltransferases (DNMTs) are a family of enzymes that methylate DNA at the C5 position of cytosine residues, and their inhibition is a promising strategy for the treatment of various developmental and proliferative diseases, particularly cancers. In the present study, a binding model for hydralazine, with a validated homology model of human DNMT, was developed by the use of automated molecular docking and molecular dynamics simulations. The docking protocol was validated by predicting the binding mode of 2'-deoxycytidine, 5-azacytidine, and 5-aza-2'-deoxycytidine. The inhibitory activity of hydralazine toward DNMT may be rationalized at the molecular level by similar interactions within the binding pocket (e.g., by a similar pharmacophore) as established by substrate-like deoxycytidine analogues. These interactions involve a complex network of hydrogen bonds with arginine and glutamic acid residues that also play a major role in the mechanism of DNA methylation. Despite the different scaffolds of other non-nucleoside DNMT inhibitors such as procaine and procainamide, the current modeling work reveals that these drugs exhibit similar interactions within the DNMT1 binding site. These findings are valuable in guiding the rational design and virtual screening of novel DNMT inhibitors.

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Anticancer Drug Discovery Targeting DNA Hypermethylation

Cited by 41 publications

References 0 publications

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

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

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Molecular Modeling and Molecular Dynamics Studies of Hydralazine with Human DNA Methyltransferase 1

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