137
Views
3
CrossRef citations to date
0
Altmetric
Research Articles

Theoretical evaluation of EGFR kinase inhibition and toxicity of di-indol-3-yl disulphides with anti-cancer potency

, &
Pages 622-634 | Received 09 Mar 2020, Accepted 23 Aug 2020, Published online: 03 Sep 2020
 

Abstract

Research aimed at developing potent di-indol-3-yl disulphides for cancer diseases makes use of various theoretical techniques to evaluate the drug-likeness parameters and the mode of action. A drug-likeness filter helps evaluate the therapeutic potency of four bis-indole derivatives, structurally related to 3,3′-methanediyl-bis-indole (DIM) but having the S-S instead of the methylene linker and showing a high inhibitory impact on the variants of cancer cell lines (among them HL-60 and DU-145). Based on in vitro experimental results for their close analogues, a correlation was found between the epidermal growth factor receptor kinase (EGFR) inhibition and the theoretical energy of complexation. Docking studies of ligands followed by molecular dynamics were performed at the ATP-binding site of EGFR tyrosine kinase to scrutinize the inhibition of the di-indol-3-yl disulphides at a molecular level. Derivatives with bromine or iodine substituents at C-5 positions of the indole moieties made strong complexes by interaction with the most important hinge region residues Met-793 and Cys-733. The inhibition model for EGFR kinase and the proposed procedures can be very informative in the biological testing of selected bis-indoles and may be useful for future research on effective inhibitors for the treatment of EGFR-related cancer.

Communicated by Ramaswamy H. Sarma

Graphical Abstract

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by the Medical University of Warsaw, Faculty of Pharmacy, under Grant FW24/NM2/17.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.