Interaction of an anticancer benzopyrane derivative with DNA: Biophysical, biochemical, and molecular modeling studies.
Benzopyrane derivatives
Circular dichroism (CD)
Double stranded DNA (dsDNA)
Isothermal titration calorimetry (ITC)
Molecular modeling
Salmon sperm DNA
Topoisomerases
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
07
01
2023
revised:
09
03
2023
accepted:
20
03
2023
medline:
25
4
2023
pubmed:
24
3
2023
entrez:
23
3
2023
Statut:
ppublish
Résumé
SIMR1281 is a potent anticancer lead candidate with multi- target activity against several proteins; however, its mechanism of action at the molecular level is not fully understood. Revealing the mechanism and the origin of multitarget activity is important for the rational identification and optimization of multitarget drugs. We have used a variety of biophysical (circular dichroism, isothermal titration calorimetry, viscosity, and UV DNA melting), biochemical (topoisomerase I & II assays) and computational (molecular docking and MD simulations) methods to study the interaction of SIMR1281 with duplex DNA structures. The biophysical results revealed that SIMR1281 binds to dsDNA via an intercalation-binding mode with an average binding constant of 3.1 × 10 The DNA binding characteristics of SIMR1281, which can disrupt/inhibit DNA function as confirmed by the topoisomerases' inhibition assays, indicate that the observed multi-target activity might originate from ligand intervention at nucleic acids level rather than due to direct interactions with multiple biological targets at the protein level. The findings of this study could be helpful to guide future optimization of benzopyrane-based ligands for therapeutic purposes.
Sections du résumé
BACKGROUND
SIMR1281 is a potent anticancer lead candidate with multi- target activity against several proteins; however, its mechanism of action at the molecular level is not fully understood. Revealing the mechanism and the origin of multitarget activity is important for the rational identification and optimization of multitarget drugs.
METHODS
We have used a variety of biophysical (circular dichroism, isothermal titration calorimetry, viscosity, and UV DNA melting), biochemical (topoisomerase I & II assays) and computational (molecular docking and MD simulations) methods to study the interaction of SIMR1281 with duplex DNA structures.
RESULTS
The biophysical results revealed that SIMR1281 binds to dsDNA via an intercalation-binding mode with an average binding constant of 3.1 × 10
CONCLUSIONS
The DNA binding characteristics of SIMR1281, which can disrupt/inhibit DNA function as confirmed by the topoisomerases' inhibition assays, indicate that the observed multi-target activity might originate from ligand intervention at nucleic acids level rather than due to direct interactions with multiple biological targets at the protein level.
GENERAL SIGNIFICANCE
The findings of this study could be helpful to guide future optimization of benzopyrane-based ligands for therapeutic purposes.
Identifiants
pubmed: 36958685
pii: S0304-4165(23)00045-4
doi: 10.1016/j.bbagen.2023.130347
pii:
doi:
Substances chimiques
DNA
9007-49-2
DNA Topoisomerases, Type II
EC 5.99.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
130347Informations de copyright
Copyright © 2023 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare competing financial interest since part of this article is in the patent application (T. H. Al-Tel, Raafat A. El-Awady, Srinivasulu Vunnam, Cijo G. Vazhapily, Hany A. Omar, Novel heterocyclic systems and pharmaceutical compositions thereof. US Patent No US20190292204A1).