Correlation Engine 2.0
Clear Search sequence regions


Sizes of these terms reflect their relevance to your search.

Chronic pain is a widespread disorder affecting millions of people and is insufficiently addressed by current classes of analgesics due to significant long-term or high dosage side effects. A promising approach that was recently proposed involves the systemic inhibition of the voltage-gated sodium channel Nav1.7, capable of cancelling pain perception completely. Notwithstanding numerous attempts, currently no drugs have been approved for the inhibition of Nav1.7. The task is complicated by the difficulty of creating a selective drug for Nav1.7, and avoiding binding to the many human paralogs performing fundamental physiological functions. In our work, we obtained a promising set of ligands with up to 5-40-fold selectivity and reaching 5.2 nanomolar binding affinity by employing a proper treatment of the problem and an innovative differential in silico screening procedure to discriminate for affinity and selectivity against the Nav paralogs. The absorption, distribution, metabolism, and excretion (ADME) properties of our top-scoring ligands were also evaluated, with good to excellent results. Additionally, our study revealed that the top-scoring ligand is a stereoisomer of an already-approved drug. These facts could reduce the time required to bring a new effective and selective Nav1.7 inhibitor to the market.

Citation

Gabriele A Trombetti, Alessandra Mezzelani, Alessandro Orro. A Drug Discovery Approach for an Effective Pain Therapy through Selective Inhibition of Nav1.7. International journal of molecular sciences. 2022 Jun 18;23(12)

Expand section icon Mesh Tags

Expand section icon Substances


PMID: 35743236

View Full Text