Molecular Modeling and Chemoinformatics to Advance the Development of Modulators of Epigenetic Targets

Prieto‐Martínez, Fernando D.; Peña‐Castillo, Andrea; Méndez‐Lucio, Oscar; Gortari, Eli Fernández-de; Medina-Franco, José L.

doi:10.1016/bs.apcsb.2016.05.001

Cited by 8 publications

(7 citation statements)

References 48 publications

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“…Interestingly, it has been proposed that the modulation of normal levels of DNMT could be conveniently achieved through the dietary uptake of food chemicals (or other "safe" natural products). A prominent example of this hypothesis has been suggested for the polyphenol compound from green tea, EGCG (Figure 1), which has been proposed to inhibit DNMT1 and reactivate methylation-silenced genes in cancer [45].…”

Section: Biochemical Dnmt Assaysmentioning

confidence: 99%

“…Of note, strong evidence indicates that environmental factors and nutrients play a major role in establishing epigenetic mechanisms, including irregular DNA methylation patterns. Thus, a regular uptake of DNA demethylating agents (which are not necessarily very potent DNMT inhibitors) is hypothesized to have a chemopreventive effect [45].…”

Section: Introductionmentioning

confidence: 99%

“…The DNMT inhibitors have been identified from different approaches or their combination [45,46] such as virtual screening [22,31], high-throughput screening, lead optimization [35,47], and structure-guided design [37], to name a few. Amongst the most promising inhibitors are molecules with "long scaffolds" such as the quinolone-based SGI-1027 (Figure 1) and analogs.…”

Section: Introductionmentioning

confidence: 99%

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Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

et al. 2020

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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.

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Section: Biochemical Dnmt Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

et al. 2020

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“…For bromodomains, recent studies have shown that the network of structural waters in the ZA channel plays a significant role on binding [19,20] and has served as a case study for the development of novel methods in the field [21]. Bromodomain inhibition is currently on an impasse [22], as chemotypes are not diverse enough to make more robust models and approaches towards their pharmacology. Hence, current efforts are focused on the synthesis and identification of plausible and novel inhibitors [23].…”

Section: Introductionmentioning

confidence: 99%

Flavonoids as Putative epi-modulators: Insights into their Binding Mode with BRD4 Bromodomain using Molecular Docking and Dynamics.

Prieto‐Martínez¹,

Medina-Franco²

2018

Preprint

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Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative and antineoplastic activities. Recently, different studies have shown that flavonoid have the potential to inhibit BET bromodomains. Previous reports suggest that flavonoids are putative inhibitors of the ZA channel due to their orientation and interactions with P86, V87, L92, L94 and N140. Herein, a comprehensive characterization of the binding mode of the biflavonoid amentoflavone and fisetin is discussed. To this end, both compounds were docked with BRD4 using four docking programs. Results were post-processed with protein-ligand interaction fingerprints. To gain further insights into the binding mode of the two natural products, docking results were further analyzed with molecular dynamics. Results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as basis for scaffold optimization and further characterization of flavonoids as BET inhibitors.

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“…Examples of techniques discussed were molecular docking, virtual screening, pharmacophore model, molecular dynamics, and similarity searching [13]. In 2016 Prieto-Martínez, et al discussed advances in computational approaches applied mostly to DNMT1 [14]. However, there are no reviews focused on the computational development on DNMT3A and 3B inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Progress on the Computational Development of Epigenetic Modulators of DNA Methyltransferases 3A and 3B

2017

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Inhibitors of DNA methyltransferases 3A and 3B (DNMT3A/3B) are promising candidates for the treatment of cancer and other diseases. Selective inhibitors of DNMT3A/3B are also attractive as small-molecule probes. During the past few years has increased significantly the research towards the development of DNMT1 inhibitors. However, there are no reviews of the recent progress in the development of small-molecule inhibitors of DNMT3A/B. Herein we review the status of inhibitors of DNMT3A/3B with emphasis on computational guided approaches. We discuss in a critical manner compound databases containing structure-activity information, crystallographic structures of DNMT3s, structure-guided studies, and virtual (<em>in silico</em>) screening coupled with experimental validation that have led to the identification or development of selective inhibitors. Perspectives in the field are also discussed.

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Molecular Modeling and Chemoinformatics to Advance the Development of Modulators of Epigenetic Targets

Cited by 8 publications

References 48 publications

Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

Expanding the Structural Diversity of DNA Methyltransferase Inhibitors

Flavonoids as Putative epi-modulators: Insights into their Binding Mode with BRD4 Bromodomain using Molecular Docking and Dynamics.

Progress on the Computational Development of Epigenetic Modulators of DNA Methyltransferases 3A and 3B

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