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. 2022 Jun 18;23(12):6793.
doi: 10.3390/ijms23126793.

A Drug Discovery Approach for an Effective Pain Therapy through Selective Inhibition of Nav1.7

Gabriele A Trombetti  1 , Alessandra Mezzelani  1 , Alessandro Orro  1
Affiliations

A Drug Discovery Approach for an Effective Pain Therapy through Selective Inhibition of Nav1.7

Gabriele A Trombetti et al. Int J Mol Sci. .

Abstract

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.

Keywords: ADME; analgesia; chronic pain; in silico drug discovery; monogenic pain disorders; paralogs; pore blocking; selectivity; voltage-gated sodium channel.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Best molecules at the end of computation.
Figure 2
Figure 2
SwissADME BOILED-Egg diagram for brain access and gastrointestinal absorption. The meaning of colors is the following: white region = high intestinal absorption, yellow region = BBB-permeant, red color = not a p-glycoprotein substrate.
Figure 3
Figure 3
ADME radar plots by SwissADME for oral bioavailability. The pink region represents suitable physicochemical space for oral bioavailability, for each of the six physicochemical parameters and for each of the top 20 ligands presented in this work.
Figure 4
Figure 4
Interactions of first-ranked ligand. (A) Interactions as shown in LigPlot+. (B) Interactions as detected by PLIP shown in ChimeraX 3D cartoon and stick representation (cross-eye stereoimage).
Figure 5
Figure 5
First-ranked ligand in its binding site as seen from outside the pore (A), from inside the pore using a section plane in light gray color (B), laterally by sectioning the pore using a section plane in light gray color (C), and as surface representation to confirm complete blocking of the pore (D) (cross-eye stereoimages).
Figure 6
Figure 6
Affinity vs. selectivity, scatterplot. (A) before the similarity search. (B) after the similarity search.
Figure 7
Figure 7
Positive target affinity change post- vs. pre-similarity search, histogram. Only refined points are shown, those that correspond to the top 1000 ligands as ranked by AS_score.
Figure 8
Figure 8
Minimization energy. Left: linear x axis. Right: logarithmic x axis.
Figure 9
Figure 9
Our lead ZINC000004073908 and Canrenone side to side, with and without chirality information.
See this image and copyright information in PMC

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