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Molecular docking study of natural alkaloids as multi-targeted hedgehog pathway inhibitors in cancer stem cell
1Centre for Chemical and Pharmaceutical Sciences, Central University of Punjab, Bathinda, PB 151001, India.
Abstract:
Cancer is responsible for millions of deaths throughout the world every year. Increased understanding as well as advancements in the therapeutic aspect seems suboptimal to restrict the huge deaths associated with cancer. The major cause responsible for this is high resistance as well as relapse rate associated with cancers. Several evidences indicated that cancer stem cells (CSC) are mainly responsible for the resistance and relapses associated with cancer. Furthermore, agents targeting a single protein seem to have higher chances of resistance than multitargeting drugs. According to the concept of network model, partial inhibition of multiple targets is more productive than single hit agents. Thus, by fusing both the premises that CSC and single hit anticancer drugs, both are responsible for cancer related resistances and screened alkaloids for the search of leads having CSC targeting ability as well as the capability to modulating multiple target proteins. The in silico experimental data indicated that emetine and cortistatin have the ability to modulate hedgehog (Hh) pathway by binding to sonic hedgehog (Hh), smoothened (Smo) and Gli protein, involved in maintenance CSCs. Furthermore, solamargine, solasonine and tylophorine are also seems to be good lead molecules targeting towards CSCs by modulating Hh pathway. Except solamargine and solasonine, other best lead molecules also showed acceptable in silico ADME profile. The predicted lead molecules can be suitably modified to get multitargeting CSC targeting agent to get rid of associate resistances.
Insights
Cancer stem cells (CSCs) drive resistance and relapse. This study screened alkaloids, identifying compounds targeting CSCs and multiple proteins, offering new strategies against cancer drug resistance.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Cancer causes millions of deaths annually, with high resistance and relapse rates contributing significantly.
- Cancer stem cells (CSCs) are implicated as a primary cause of treatment resistance and cancer recurrence.
- Conventional single-target therapies often face resistance, whereas multitargeting agents show greater promise.
Purpose of the Study:
- To identify novel alkaloid-based lead compounds with cancer stem cell (CSC) targeting capabilities.
- To explore compounds that can modulate multiple protein targets, addressing drug resistance.
- To investigate the potential of network-based therapeutic strategies against cancer.
Main Methods:
- In silico screening of alkaloids for CSC-targeting potential.
- Evaluation of compounds for their ability to modulate multiple protein targets within cancer pathways.
- Assessment of in silico Absorption, Distribution, Metabolism, and Excretion (ADME) profiles.
Main Results:
- Emetine and cortistatin were identified as potential modulators of the hedgehog (Hh) pathway, targeting key CSC maintenance proteins (Hh, Smo, Gli).
- Solamargine, solasonine, and tylophorine also showed promise in targeting CSCs via Hh pathway modulation.
- Several lead molecules exhibited acceptable in silico ADME profiles, suggesting potential for drug development.
Conclusions:
- Alkaloids targeting CSCs and multiple proteins, particularly via the Hh pathway, represent a promising strategy to overcome cancer resistance.
- Identified lead compounds like emetine, cortistatin, solamargine, solasonine, and tylophorine warrant further investigation and modification into multitargeting agents.
- Developing multitargeting CSC-targeting agents could significantly improve therapeutic outcomes and reduce cancer-related mortality.
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