QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors

Authors

  • Chuleeporn Phanus-umporn Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
  • Veda Prachayasittikul Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand. Phone: +66 2 441 4371; Fax: +66 2 441 4380; E-mail: veda.pra@mahidol.ac.th
  • Chanin Nantasenamat Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
  • Supaluk Prachayasittikul Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
  • Virapong Prachayasittikul Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand

DOI:

https://doi.org/10.17179/excli2020-1096

Keywords:

DNA methyltransferase 1, QSAR, computer-aided drug design, rational design, structural modification, epigenetic modulators

Abstract

DNA methylation, an epigenetic modification, is mediated by DNA methyltransferases (DNMTs), a family of enzymes. Inhibitions of these enzymes are considered a promising strategy for the treatment of several diseases. In this study, a quantitative structure-activity relationship (QSAR) modeling was employed to understand the structure-activity relationship (SAR) of currently available non-nucleoside DNMT1 inhibitors (i.e., indole and oxazoline/1,2-oxazole scaffolds). Two QSAR models were successfully constructed using multiple linear regression (MLR) and provided good predictive performance (R2Tr = 0.850-0.988 and R2CV = 0.672-0.869). Bond information content index (BIC1) and electronegativity (R6e+) are the most influential descriptors governing the activity of compounds. The constructed QSAR models were further applied for guiding a rational design of novel inhibitors. A novel set of 153 structurally modified compounds were designed in silico according to the important descriptors deduced from the QSAR finding, and their DNMT1 inhibitory activities were predicted. This result demonstrated that 86 newly designed inhibitors were predicted to elicit enhanced DNMT1 inhibitory activity when compared to their parent compounds. Finally, a set of promising compounds as potent DNMT1 inhibitors were highlighted to be further developed. The key SAR findings may also be beneficial for structural optimization to improve properties of the known inhibitors.

Downloads

Published

2020-04-02

How to Cite

Phanus-umporn, C., Prachayasittikul, V., Nantasenamat, C., Prachayasittikul, S., & Prachayasittikul, V. (2020). QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors. EXCLI Journal, 19, 458–475. https://doi.org/10.17179/excli2020-1096

Issue

Vol. 19 (2020)

Section

Original articles

License

Authors who publish in this journal agree to the following terms:

  • The authors keep the copyright and grant the journal the right of first publication under the terms of the Creative Commons Attribution license, CC BY 4.0. This licencse permits unrestricted use, distribution and reproduction in any medium, provided that the original work is properly cited.
  • The use of general descriptive names, trade names, trademarks, and so forth in this publication, even if not specifically identified, does not imply that these names are not protected by the relevant laws and regulations.
  • Because the advice and information in this journal are believed to be true and accurate at the time of publication, neither the authors, the editors, nor the publisher accept any legal responsibility for any errors or omissions presented in the publication. The publisher makes no guarantee, express or implied, with respect to the material contained herein.
  • The authors can enter into additional contracts for the non-exclusive distribution of the journal's published version by citing the initial publication in this journal (e.g. publishing in an institutional repository or in a book).

Most read articles by the same author(s)

<< < 1 2 3 4 > >>