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From Natural Products to Drugs for Epimutation Computer-Aided Drug Design

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Abstract

The epimutational event, i.e., ectopic methylation in tumor suppressor genes, can lead to gene silencing, thus promoting prognosis of cancer. The progression of DNA methylation is a cycle of demethylation, de novo methylation, and maintenance methylation. The enzyme responsible for maintenance of methylation status is DNA methyltransferase 1 (DNMT1), the continuous activity of which is required to maintain the pattern of epimutation; thus, its inhibition is a promising strategy for the treatment of cancer. To the best of our knowledge, this study is the first to focus on the recently developed crystal structure of the catalytic site of DNMT1. Here in this study, we have used the crystal structure for the development of non-nucleoside DNMT1 inhibitors using virtual screening (VS), absorption, distribution, metabolism, elimination/toxicology analysis, and molecular docking studies. In this study, VS was carried out on 48,531 natural products to create a subset of lead-like natural products. Three of them were found to form hydrogen bonds with the catalytic site of the DNMT1 (Cys 1226). Thus, this study adumbrates potential lead compounds for treatment of epimutation.

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Acknowledgments

We would like to sincerely thank VIT University for providing the facilities for this research.

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Authors and Affiliations

  1. School of Bioscience and Technology, VIT University, Vellore, Tamil Nadu, India

    Naveed A. Chikan, V. Bhavaniprasad, K. Anbarasu & Trupti N. Patel

  2. Department of Animal Biotechnology, College of Veterinary Sciences and Animal Husbandry, Anand Agricultural University, Anand, Gujarat, India

    Nadeem Shabir

  3. Division of Medical Biotechnology, SBST, VIT, Vellore, 632014, Tamilnadu, India

    Trupti N. Patel

Authors
  1. Naveed A. Chikan
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  2. V. Bhavaniprasad
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  3. K. Anbarasu
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  5. Trupti N. Patel
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Correspondence to Trupti N. Patel.

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Chikan, N.A., Bhavaniprasad, V., Anbarasu, K. et al. From Natural Products to Drugs for Epimutation Computer-Aided Drug Design. Appl Biochem Biotechnol 170, 164–175 (2013). https://doi.org/10.1007/s12010-013-0158-6

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  • DOI: https://doi.org/10.1007/s12010-013-0158-6

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