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Identification of small molecule inhibitors against doublecortin-like kinase 1 for targeting colon cancer stem cells

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Title Identification of small molecule inhibitors against doublecortin-like kinase 1 for targeting colon cancer stem cells
 
Creator L, Lizha Mary
Gor, Ravi
T, Anand
V, Sivaramakrishnan
R, Satish
 
Subject Molecular docking
Molecular simulation
Protein-ligand interaction
SwissADME
Traditional chinese
medicine database
Virtual screening
 
Description 552-562
As per the World Health Organisation (WHO) reports, colon cancer ranks second among cancer types affecting women,
and third among those affecting men. An evolving hypothesis in the field of oncogenesis posits that a limited population of
quiescent cells can give rise to primary tumors. The investigation of cancer stem cells (CSCs) offers a potential avenue for
devising innovative approaches to cancer therapy. Notably, the identification of doublecortin-like kinase 1 (DCLK1) assumes
significance as it serves as a distinctive marker for CSCs in pancreatic and colon cancer contexts. Nevertheless, the clinical
translation of silencing DCLK1 via small interfering RNA (siRNA) encounters various pragmatic impediments. Consequently,
the pursuit of specific inhibitors targeting DCLK1 emerges as a promising strategy for impeding the processes of cancer
initiation, progression, and metastasis, partly by modulating epithelial-mesenchymal transition (EMT) and inducing CSC
apoptosis. In this study, our investigation involved querying a repository of traditional Chinese medicinal compounds to discern
potential small molecules exhibiting affinity for DCLK1. The compound that displayed the most favorable attributes, luteolin,
was subsequently subjected to molecular dynamics simulations. Our computational analysis unveiled luteolin's remarkable
qualities, characterized by its conspicuously low binding energy and heightened affinity for the DCLK1 protein. Notably, the
simulation divulged a sustained and intricate binding interaction between luteolin and the DCLK1 protein, involving a range of
one to four hydrogen bonds throughout the simulation's 100 nanoseconds trajectory. Furthermore, the minimal root mean square
deviation observed throughout the simulation duration indicates the stability of the DCLK1-luteolin complex. The identification
and validation of distinct inhibitors targeting DCLK1 possess the potential to transform extant approaches to cancer treatment.
By exerting control over EMT and instigating the death of CSCs, these inhibitors could aid in transformative changes in the
landscape of cancer therapy strategies.
 
Date 2024-08-29T10:15:19Z
2024-08-29T10:15:19Z
2024-08
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://nopr.niscpr.res.in/handle/123456789/64461
https://doi.org/10.56042/ijbb.v61i9.5930
 
Language en
 
Publisher NIScPR-CSIR,India
 
Source IJBB Vol.61(09) [September 2024]