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Potential protein kinase inhibitors that target G-quadruplex DNA structures in the human telomeric regions

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Abstract

Telomeric regions contain Guanine-rich sequences arranged in a planar manner and connected by Hoogsteen hydrogen bonds that can fold into G-quadruplex (G4) DNA structures, and can be stabilized by monovalent metal cations. The presence of G4 DNA holds significance in cancer-related processes, especially due to their regulatory potential at transcriptional and translational levels of oncogene and tumor suppressor genes. The objective of this current research is to explore the evolving realm of FDA-approved protein kinase inhibitors, with a specific emphasis on their capacity to stabilize the G4 DNA structures formed at the human telomeric regions. This involves investigating the possibility of repurposing FDA-approved protein kinase inhibitors as a novel approach for targeting multiple cancer types. In this context, we have selected 16 telomeric G4 DNA structures as targets and 71 FDA-approved small-molecule protein kinase inhibitors as ligands. To investigate their binding affinities, molecular docking of human telomeric G4 DNA with nuclear protein kinase inhibitors and their corresponding co-crystalized ligands were performed. We found that Ponatinib and Lapatinib interact with all the selected G4 targets, the binding free energy calculations, and molecular dynamic simulations confirm their binding efficacy and stability. Thus, it is hypothesized that Ponatinib and Lapatinib may stabilize human telomeric G4 DNA in addition to their ability to inhibit BCR-ABL and the other members of the EGFR family. As a result, we also hypothesize that the stabilization of G4 DNA might represent an additional underlying mechanism contributing to their efficacy in exerting anti-cancer effects.

Graphical abstract

Stabilizing G4 structures at the human telomeric regions by the FDA-approved kinase inhibitors that targets nuclear kinases.

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Abbreviations

G4:

G-quadruplex

hTERT:

Human telomerase reverse transcriptase

CML:

Chronic myeloid leukemia

PDB:

Protein data bank

SDF:

Structure data file

RMSD:

Root mean square deviation

OPLS4:

Optimized potential for liquid simulations

XP:

Extra precision

MMGBSA:

Molecular mechanics with generalized born and surface area solvation

VGSB:

Variable dielectric surface generalised born

CgenFF:

CHARMM general force field

NVT:

Number of particles, volume, and temperature

NPT:

Number of particles, pressure, and temperature

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Acknowledgements

We thank the Yenepoya (Deemed to be University) for the facility support to the Centre for Integrative Omics Data Science (CIODS). Amjesh Revikumar is a recipient of a national post-doctoral fellowship (PDF/2017/001652) and Rajesh Raju is a recipient of the Young Scientist Award (YSS/2014/000607) from the Science and Engineering Research Board, Department of Science and Technology (DST), Government of India.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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  1. Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to Be University), Mangalore, Karnataka, 575018, India

    Bhavya Banjan, Abel John Koshy, Haritha Kalath, Levin John, Sowmya Soman, Rajesh Raju & Amjesh Revikumar

  2. Kerala Genome Data Centre, Kerala Development and Innovation Strategic Council, Vazhuthacaud, Thiruvananthapuram, Kerala, 695014, India

    Amjesh Revikumar

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Contributions

AR: developed the original hypothesis for the work. AR and BB: developed the computational workflow and wrote the initial draft of the manuscript. BB, AJK, and HK: did the Molecular docking and dynamics studies. LJ: developed the graphical contents in the manuscript. SS, RR: critically evaluated the manuscript and ensured that the study’s scientific aspect was rationally valid. All authors read, edited, and approved the final manuscript.

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Correspondence to Rajesh Raju or Amjesh Revikumar.

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Banjan, B., Koshy, A.J., Kalath, H. et al. Potential protein kinase inhibitors that target G-quadruplex DNA structures in the human telomeric regions. Mol Divers (2024). https://doi.org/10.1007/s11030-023-10768-7

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  • DOI: https://doi.org/10.1007/s11030-023-10768-7

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