Interaction of DisBa01 peptide from Bothrops alternatus venom with BRAF melanoma receptors: Modeling and molecular
Tatiane Senna Bialves1, Luana Luiza Bastos2, John Alexanders Amaya Parra3
1Graduate Program in Physiological Sciences (PPGCF), Federal University of Rio Grande - FURG, Av. Italy, s/n - km 8 - Carreiros, Rio Grande, Rio Grande do Sul, Brazil.
Abstract:
Metastatic melanoma is highly aggressive and challenging, often leading to a grim prognosis. Its progression is swift, especially when mutations like BRAFV600E continuously activate pathways vital for cell growth and survival. Although several treatments target this mutation, resistance typically emerges over time. In recent decades, research has underscored the potential of snake venoms and peptides as bioactive substances for innovative drugs, including anti-coagulants, anti-microbial, and anti-cancer agents. Leveraging this knowledge, we propose employing a bioinformatics simulation approach to: a) Predict how well a peptide (DisBa01) from Bothrops alternatus snake venom binds to the melanoma receptor BRAFV600E via Molecular Docking. b) Identify the specific peptide binding sites on receptors and analyze their proximity to active receptor sites. c) Evaluate the behavior of resulting complexes through molecular dynamics simulations. d) Assess whether this peptide qualifies as a candidate for anti-melanoma therapy. Our findings reveal that DisBa01 enhances stability in the BRAFV600E melanoma receptor structure by binding to its RGD motif, an interaction absent in the BRAF WT model. Consequently, both docking and molecular dynamics simulations suggest that DisBa01 shows promise as a BRAFV600E inhibitor.
Insights
Snake venom peptide DisBa01 shows promise in inhibiting BRAFV600E, a key driver of metastatic melanoma. This peptide enhances the stability of the BRAFV600E receptor, offering a potential new avenue for anti-melanoma therapy.
Area of Science:
- Biochemistry
- Bioinformatics
- Pharmacology
Background:
- Metastatic melanoma is an aggressive cancer with poor prognosis, often driven by BRAFV600E mutations.
- Acquired resistance to targeted therapies necessitates novel therapeutic strategies.
- Snake venom peptides are recognized for their diverse bioactive properties, including anti-cancer potential.
Purpose of the Study:
- To investigate the binding affinity of the snake venom peptide DisBa01 to the BRAFV600E melanoma receptor using bioinformatics simulations.
- To identify peptide binding sites and analyze their interaction with active receptor sites.
- To evaluate the therapeutic potential of DisBa01 as an anti-melanoma agent.
Main Methods:
- Molecular docking simulations to predict peptide-receptor binding.
- Analysis of peptide binding site interactions and proximity to active sites.
- Molecular dynamics simulations to assess the stability of peptide-receptor complexes.
Main Results:
- DisBa01 effectively binds to the BRAFV600E receptor, specifically interacting with its RGD motif.
- This binding interaction was not observed in the wild-type BRAF model.
- Molecular dynamics simulations indicated enhanced stability of the BRAFV600E-DisBa01 complex.
Conclusions:
- DisBa01 demonstrates significant potential as an inhibitor of the BRAFV600E mutation in melanoma.
- The peptide's interaction with the RGD motif suggests a specific mechanism of action.
- DisBa01 warrants further investigation as a candidate for novel anti-melanoma therapies.
