Related Experiment Video
Updated: May 31, 2025
Advanced Glycation End-Products Sensitize Human Sensory-Like Neuron Cells to Capsaicin-Induced Calcium Influx
Published on: May 2, 2025
Ononin's Antagonistic Activity towards TRPV1: Insights from Molecular Dynamics and Capsaicin-Evoked Calcium Response
Fadi G Saqallah1, Manal A Abbas2, Belal O Al-Najjar3,4
1Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, 11733, Jordan.
Background:
The search for effective painkillers has led to intensive research, with a particular focus on the transient receptor potential vanilloid-1 (TRPV1) channel as a possible target.
Methods:
One promising candidate is ononin, which is investigated for its binding with TRPV1 through a 200-ns molecular dynamic simulation and analysed via root-meansquare deviation (RMSD), root-mean-square fluctuation (RMSF), hydrogen-bond interactions, radius of gyration (RadGyr), and MM-PBSA energy calculations. The results were further validated experimentally via calcium imaging studies.
Results:
Molecular dynamics revealed that the ononin-TRPV1 complex achieved stable binding within a remarkably short time of approximately 38 ns while maintaining the degree of compactness of the receptor throughout a 200 ns simulation period. In contrast, the capsazepine-TRPV1 complex displayed more significant structural deviations during the whole simulation. Moreover, MM-PBSA energy calculations showed a relatively strong binding affinity between ononin and TRPV1, mainly attributed to favourable hydrophobic interactions. Pre-incubation of dorsal root ganglia (DRG) neurons with ononin (1 and 10 μM) or capsazepine (10 μM) for 4 min prior to stimulation with capsaicin significantly reduced capsaicin-evoked calcium responses. No significant difference between capsazepine and ononin was found at a concentration of 10 μM.
Conclusion:
Overall, this research demonstrates the potential of ononin as a potential antagonist for developing analgesics targeting TRPV1. Hence, and to our best knowledge, this study represents the first report of ononin's antagonistic activity towards TRPV1.
Insights
Ononin shows potential as a novel painkiller by acting as a TRPV1 channel antagonist. This study provides the first evidence of ononin
Area of Science:
- Pharmacology and Molecular Biology
- Computational Chemistry
- Neuroscience
Background:
- Intensive research is underway to discover effective painkillers.
- The transient receptor potential vanilloid-1 (TRPV1) channel is a key target for pain management.
- Ononin is explored as a potential therapeutic agent modulating TRPV1 activity.
Purpose of the Study:
- To investigate the binding interaction between ononin and the TRPV1 channel.
- To evaluate the potential of ononin as a TRPV1 antagonist for analgesic drug development.
- To provide the first report on ononin's antagonistic activity against TRPV1.
Main Methods:
- A 200-ns molecular dynamics simulation was performed to analyze ononin-TRPV1 complex stability and interactions.
- Key analytical techniques included RMSD, RMSF, hydrogen-bond analysis, radius of gyration, and MM-PBSA energy calculations.
- Experimental validation was conducted using calcium imaging studies on dorsal root ganglia (DRG) neurons.
Main Results:
- The ononin-TRPV1 complex exhibited stable binding within 38 ns, maintaining receptor compactness throughout the 200 ns simulation.
- MM-PBSA calculations indicated strong binding affinity between ononin and TRPV1, driven by hydrophobic interactions.
- Ononin, similar to capsazepine, significantly reduced capsaicin-evoked calcium responses in DRG neurons.
Conclusions:
- Ononin demonstrates potential as a TRPV1 antagonist for developing novel analgesics.
- This study is the first to report ononin's antagonistic activity towards the TRPV1 channel.
- The findings support further investigation of ononin for pain management therapies.
Related Concept Videos
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
01:12Mechanically-gated Ion Channels
01:19The Role of Ion Channels in Neuronal Computation
Sometimes a single EPSP is strong enough to induce an action potential in the postsynaptic neuron. However, multiple presynaptic inputs must often create EPSPs around the same time for the postsynaptic neuron to be sufficiently depolarized to fire an action potential....