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In silico study of the synergistic anti-tumor effect of hybrid topoisomerase-HDAC inhibitors

  • Kriti Kashyap and Rita Kakkar EMAIL logo
Published/Copyright: June 22, 2021
Pure and Applied Chemistry
From the journal Pure and Applied Chemistry Volume 93 Issue 10

Abstract

Combination therapies that include treatment of cancerous cells with histone deacetylase (HDACs) inhibitors prior to treatment with topoisomerase inhibitors have shown synergistic anti-tumor effects. The promising results of such combination therapies have led to the development of a novel class of multitarget hybrid inhibitors that are designed by merging the scaffolds of topoisomerase and HDAC inhibitors, which consequently inhibit both classes of cancer-inducing targets simultaneously. These multitarget hybrids also have pharmacokinetic advantages over the traditional combinatorial approach, which struggles with disadvantages like maintaining optimum concentrations of multiple toxic drugs, which in turn leads to enhanced toxicity and other side-effects associated with the multiple drugs administered. Binding modes of some Top-HDAC hybrids have been predicted with the help of molecular docking in order to understand the binding of such hybrids with their target receptors and to identify the structural determinants responsible for their synergistic anti-tumor effect. Extra precision docking of Top1-HDAC and Top2-HDAC hybrid inhibitors has been carried out with Top1-DNA, Top2-DNA, HDAC1 and HDAC6 receptor structures. A detailed analysis of the molecular interactions of the hybrids with the target receptor binding sites has been undertaken and their predicted binding modes have been compared with the crystal binding modes of their component drugs. An explanation for the apparent selectivity of the hybrids towards HDAC6 has also been provided.

Keywords: Antitumor activity; bioactive molecules; chemistry and its applications; computational chemistry; enzyme inhibitors; hydrogen bonding; medicinal chemistry; modeling; molecular mechanics; protein interactions; structure-activity; VCCA-2020
Corresponding author: Rita Kakkar, Computational Chemistry Laboratory, Department of Chemistry, University of Delhi, New Delhi, 110007, Delhi, India, e-mail:

Article note: A collection of invited papers based on presentations at the Virtual Conference on Chemistry and its Applications (VCCA-2020) held on-line, 1–31 August 2020.

Funding source: University Grants Commission 10.13039/501100001501

Award Identifier / Grant number: 22/06/2014(i)EU-V

Acknowledgement

Kriti Kashyap thanks the University Grants Commission (UGC) for a research fellowship.

  1. Research funding: Senior research fellowship from University Grants Commission (Grant Reference ID: 22/06/2014(i)EU-V).

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/pac-2021-0111).

Published Online: 2021-06-22
Published in Print: 2021-10-26

© 2021 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/

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https://doi.org/10.1515/pac-2021-0111
Keywords for this article
Antitumor activity; bioactive molecules; chemistry and its applications; computational chemistry; enzyme inhibitors; hydrogen bonding; medicinal chemistry; modeling; molecular mechanics; protein interactions; structure-activity; VCCA-2020

Articles in the same Issue

  1. Frontmatter
  2. In this issue
  3. Preface
  4. Celebrating a centenary of macromolecules
  5. Invited papers
  6. Hermann Staudinger – Organic chemist and pioneer of macromolecules
  7. On cellulose spatial organization and interactions as unraveled by diffraction and spectroscopic methods throughout the 20th century
  8. Dielectric properties of processed cheese
  9. Drawing inspiration from nature to develop anti-fouling coatings: the development of biomimetic polymer surfaces and their effect on bacterial fouling
  10. Mitigating the charge trapping effects of D-sorbitol/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) polymer blend contacts to crystalline silicon
  11. Influence of thermal treatment on the properties and intermolecular interactions of epoxidized natural rubber-salt systems
  12. Leveraging diversity and inclusion in the polymer sciences: the key to meeting the rapidly changing needs of our world
  13. Preface
  14. The virtual conference on chemistry and its applications, VCCA-2020, 1–31 August 2020
  15. Conference papers
  16. Effect of non-competitive inhibitors of aminopeptidase N on viability of human and murine tumor cells
  17. Evaluation of the catalytic activity of graphene oxide and zinc oxide nanoparticles on the electrochemical sensing of T1R2-Rebaudioside A complex supported by in silico methods
  18. Maximizing student learning through the use of demonstrations
  19. Molecular spaces and the dimension paradox
  20. Reaction of •OH with CHCl=CH-CHF2 and its atmospheric implication for future environmental-friendly refrigerant
  21. In silico study of the synergistic anti-tumor effect of hybrid topoisomerase-HDAC inhibitors
  22. Structural and electronic properties of Cu4O3 (paramelaconite): the role of native impurities
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