21 May 2020
This is how painkillers can become “smarter”
Published online 13 January 2016
Insights into how natural pain-relievers work may help develop “smarter” painkillers.
Researchers have discovered how two naturally occurring pain-relieving compounds bind to a specific ion channel in pain-sensing nerve cells. This discovery is potentially useful for designing better and safer painkillers, they say.
Using advanced computational techniques, the researchers, including Khaled Elokely from Tanta University, Egypt, have explored the different binding modes of capsaicin (CAPS) and resiniferatoxin (RTX) with the ion channel known as TRPV11.
TRPV1 is activated by painful stimuli such as heat, pH and some toxins. CAPS and RTX can bind to TRPV1 and activate it, which desensitizes the channel and ultimately leads to analgesia.
Computational predictions were confirmed by mutagenesis experiments, identifying the amino acids essential to binding CAPS and RTX. This also allowed the authors to predict the binding of an additional 96 ligands, and to suggest chemical modifications for the synthesis of more molecules binding more effectively to TRPV1.
“The accurate binding modes of CAPS and RTX would pave the development of potential drug candidates that could work by blocking or weakening the activity of TRPV1, eventually reducing pain,” says lead researcher Vincenzo Carnevale from Temple University, US.
- Elokely, K. et al. Understanding TRPV1 activation by ligands: insights from the binding modes of capsaicin and resiniferatoxin. Proc. Natl Acad. Sci. http://dx.doi.org/10.1073/pnas.1517288113 (2015).