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2646: NaV1.7 Round 2

Closed since 7 months ago

Intermediate Overall Small Molecule Design

Summary

Created
August 08, 2025
Expires
Max points
100
Description

NaV1.7 is a voltage-gated sodium channel that plays a key role in the generation and propagation of action potentials, especially in neurons involved in pain signaling. Genetic studies have revealed that loss-of-function mutations in NaV1.7 can result in congenital insensitivity to pain, while gain-of-function mutations are associated with severe, painful disorders. This makes NaV1.7 a promising therapeutic target for the development of non-addictive painkillers—a much-needed alternative to current opioid-based treatments.

In this puzzle, your goal is to design small molecules that bind selectively to Voltage Sensing Domain IV (VSD4) of NaV1.7 in its activated conformation. The VSDs act as regulatory switches for the channel, and locking VSD4 in its active state helps stabilize the entire channel in an activated non-conductive conformation. The starting molecule, originally developed by Genentech, reached clinical trials but ultimately failed—leaving room for better, more effective designs.

One challenge is that VSD4 is embedded in the lipid membrane, so you’ll need to carefully consider the surrounding lipid environment. Ideal molecules should engage the target deeply and specifically without protruding excessively into the membrane, which could compromise target engagement in vivo.

Your creativity and intuition could lead to a breakthrough—you might just design the next-generation analgesic to transform how we treat pain!

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Comments

Sciren Staff Lv 1

Objectives

Maximum bonus: +10000

Compound Library (max +2000)
Gives a bonus if your current compound is in the library. This uses a local cached version of the Compound Library search results to determine if the compound is in the library. If you manually create a compound that happens to be in the library (or if you load a shared solution with an on-library compound), you may need to submit the compound to the compound library search and wait to get the results back before the objective can properly recognize that the compound is in the library. (If the objective is not updating, try wiggling the structure. See this forum post for more discussion.)

Torsion Quality (max +1000)
Keeps bond rotations in a good range. Using Wiggle or Tweak Ligand can fix bad torsions. (Show highlights torsions to be rotated.)

Number of Rotatable Bonds (max +1000)
Intended to keep the ligand from getting too big and floppy. You can reduce rotatable bonds by deleting groups or forming rings. (Show highlights rotatable bonds.)

Ligand TPSA (max +1000)
Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens. (Show highlights atoms contributing to higher TPSA.)

Ligand cLogP (max +1000)
A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens. (Show highlights atoms contributing to higher cLogP.)

Fraction of four-bonded carbons (max +1000)
Measures how carbons with bonds to four atoms ("sp3 hybridized") there are. Too few (too many double and triple bonded carbons) is bad. (Show highlights carbon atoms at issue.)

Bad Groups (max +1000)
Gives a bonus for avoiding groups that interfere with assays, which are far from the compounds in the library, or which otherwise have issues. (Show highlights groups at issue.)

Molecular Weight (max +1000)
Keeps the ligand within a reasonable size limit.

Synthetic Accessibility (max +1000)
Keeps the ligand from going too far from the compounds in the library. (Show highlights parts of the molecule at issue.)