Related Experiment Video
Updated: May 15, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
A computational perception of BBOX1-IP3R3 interaction uncovers inhibitors for dysregulated calcium signalling in
P Sangavi1,2, G R Shri3, S K Singh3
1Department of Bioinformatics, Alagappa University, Karaikudi, India.
Abstract:
Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer unveiling negative expression on oestrogen receptors, progesterone receptors, and HER2. The anomalous activation of signalling pathways and specific types of mutations characterize the progression of TNBC. Protein-protein interaction in the tumour microenvironment plays a crucial role in tumour aggressiveness. Disrupting the signalling pathways that promote cell progression, migration, and survival opens up a promising avenue for targeting the aggressive form of TNBC. The present study emphasizes the molecular interaction mechanism driving the aggressive and recalcitrant TNBC between BBOX1-IP3R3. The BBOX1-IP3R3 complex destabilization was accomplished using compounds obtained from various databases through virtual screening, molecular, and essential dynamics. The interaction study revealed that the four hits bound at the interface and facilitated better binding affinity with the highest docking score and optimal binding free energy. In addition, the molecular dynamics simulation, PCA/FEL, and MM/PBSA analysis conclusively evaluate the binding potential of the compounds and unequivocally stabilize specific conformations or deception of the complexes in high-energy states. Thus, the identified compounds lead to the disruption of BBOX1-IP3R3 interaction, which aids in the therapeutic option of TNBC.
Insights
Researchers identified compounds that disrupt the BBOX1-IP3R3 interaction, offering a new therapeutic strategy for aggressive Triple Negative Breast Cancer (TNBC). This approach targets key molecular mechanisms driving tumor progression.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- Triple Negative Breast Cancer (TNBC) is an aggressive breast cancer subtype lacking estrogen, progesterone, and HER2 receptors.
- Tumor microenvironment protein-protein interactions significantly influence TNBC aggressiveness and progression.
- Targeting signaling pathways crucial for cancer cell survival and migration is a key therapeutic strategy for TNBC.
Purpose of the Study:
- To investigate the molecular interaction mechanism between BBOX1 and IP3R3 in Triple Negative Breast Cancer.
- To identify potential therapeutic compounds that disrupt the BBOX1-IP3R3 complex using computational methods.
- To evaluate the binding affinity and stability of identified compounds through molecular dynamics simulations.
Main Methods:
- Virtual screening of compound databases to identify potential BBOX1-IP3R3 inhibitors.
- Molecular docking and binding free energy calculations to assess compound efficacy.
- Molecular dynamics (MD) simulations, Principal Component Analysis (PCA), Free Energy Landscape (FEL), and Molecular Mechanics with the Poisson-Boltzmann Surface Area (MM/PBSA) analysis to evaluate binding stability and conformational changes.
Main Results:
- Four compounds were identified through virtual screening that effectively bind to the BBOX1-IP3R3 interface.
- These compounds exhibited high binding affinity, favorable docking scores, and optimal binding free energy.
- MD simulations and subsequent analyses confirmed the compounds' potential to destabilize the BBOX1-IP3R3 complex and stabilize high-energy conformations.
Conclusions:
- The identified compounds effectively disrupt the BBOX1-IP3R3 interaction, a critical mechanism in aggressive TNBC.
- These compounds represent promising candidates for developing novel therapeutic strategies against Triple Negative Breast Cancer.
- Targeting the BBOX1-IP3R3 complex offers a viable approach for treating recalcitrant TNBC cases.
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