KCNQ1: A Quest to Combat Long QT Syndrome

Started by Sciren

Sciren Staff Lv 1

We are excited to introduce a new challenge, centered around the KCNQ1 gene and its significant role in heart health. KCNQ1 encodes the Kv7.1 voltage-gated potassium ion channel, a crucial player in regulating the heart's rhythm. When mutations occur in this channel, they can lead to serious cardiac conditions, such as congenital long QT syndrome (LQTS). This inherited arrhythmia affects about one in every 2,000 live births and poses a heightened risk of sudden cardiac death, especially in young patients.

Our mission is to find new therapeutics to treat LQTS, focusing on activators of the KCNQ1 channel. One promising compound, ML277, was identified from a large-scale screening of 300,000 compounds. Extensive research revealed key insights into its structure and function:

  • Structural Importance of 4-(4-methoxyphenyl)thiazole: This part of the molecule is crucial for its activity. Any changes to the 4-(4-methoxyphenyl)thiazole part rendered ML277 inactive, meaning it lost its ability to activate the KCNQ1 channel. This highlights the importance of this specific chemical structure in maintaining the compound's function.
  • Chirality and Activity: ML277 has two forms, known as isomers, which are like mirror images of each other. The (R)-isomer is the active form that effectively activates the KCNQ1 channel. The other form, the (S)-isomer, does not have this activating effect. This demonstrates the significance of the molecule's 3D shape in its function.
  • Role of the Tolyl Group: The tolyl group, a specific part of ML277, was identified as the most effective part of the molecule. This group interacts favorably with the KCNQ1 channel, contributing significantly to the compound's ability to activate the channel.

Recent CryoEM studies have provided a detailed view of how ML277 interacts with KCNQ1, helping us understand its role as an activator. ML277 fits snugly alongside a specific helix linker in the KCNQ1 channel, causing it to open and restore proper function. It will be a good idea to keep these areas in mind as both the thiazole and the tolyl group create hydrophobic interactions with KCNQ1. That being said, it is not explicitly necessary to preserve these as exploration in the chemical space is important.

  • Enlarged side view of the ML277 binding pocket formed by the S4-S5 linker helix.
  • Willegems, K., Eldstrom, J., Kyriakis, E. et al. Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277. Nat Commun 13, 3760 (2022). https://doi.org/10.1038/s41467-022-31526-7

For this puzzle, our goal is to design a new KCNQ1 activator that can restore function in KCNQ1 variants associated with LQTS. We started with a virtual screening of a massive library containing 36 billion compounds and narrowed it down to less than 900 candidates. These compounds were selected for their potential to interact effectively with KCNQ1 at the ML277 binding site. Since extensive research has been done to optimize ML277, we will be using some of these other candidates as starting molecules in this puzzle series to help broaden the search and development efforts.

Now, it's your turn to join the quest! Since scientists are still working on a therapeutic intervention for LQTS, and their primary guide, currently is ML277, it is important to help their efforts by finding other promising compounds that bind with KCNQ1. Help us discover a new activator that could make a real difference in the lives of those affected by LQTS. Let's work together to unlock the potential of KCNQ1 and bring new hope to those with this challenging condition!

jeff101 Lv 1

@spvincent, which groups do you mean? Do you mean the thiazole and tolyl groups?

"It will be a good idea to keep these areas in mind as both the thiazole and the tolyl group create hydrophobic interactions with KCNQ1. That being said, it is not explicitly necessary to preserve these as exploration in the chemical space is important."

jeff101 Lv 1

Are the Foldit images above for ML277 correct? One search for ML277 gave the web page
https://www.tocris.com/products/ml-277_4777 which shows a different structure from above.
This web page also says that ML277 has Molecular Weight 471.59, C23H25N3O4S2,
(2R)-N-[4-(4-Methoxyphenyl)-2-thiazolyl]-1-[(4-methylphenyl)sulfonyl]-2-piperidinecarboxamide,
CAS 1401242-74-7, PubChem ID 53347902, InCHI Key OXQNLLVUVDAEHC-OAQYLSRUSA-N, and
SMILES code O=[C@@]([C@H]3CCCCN3S(C4=CC=C(C)C=C4)(=O)=O)NC1=NC(C2=CC=C(OC)C=C2)=CS1.

jeff101 Lv 1

I think the Foldit images above have -O-CH2CH3 instead of -O-CH3 at one end.
I think they also have an extra -CH2- group between -NH-(C=O)- and the twisted 6-membered-ring.

jeff101 Lv 1

When I put the tocris site's SMILES code O=[C@@]([C@H]3CCCCN3S(C4=CC=C(C)C=C4)(=O)=O)NC1=NC(C2=CC=C(OC)C=C2)=CS1 into the box above the Molecular Editor at https://zinc20.docking.org/substances/home/ it was converted to the SMILES code COc4ccc(c3csc(NC(=O)[C@H]1CCCCN1S(=O)(=O)c2ccc(C)cc2)n3)cc4 which led to the web page https://zinc20.docking.org/substances/chemicalize/?smiles=COc4ccc%28c3csc%28NC%28%3DO%29%5BC%40H%5D1CCCCN1S%28%3DO%29%28%3DO%29c2ccc%28C%29cc2%29n3%29cc4 which gave Mwt 471.604, logP 4.309, 32 heavy atoms, and no ZINC ID #. Counting the heavy atoms gave 23 C, 4 O, 3 N, and 2 S (32 heavy atoms in all).

Below is the image the ZINC20 site gave:Below is the image the tocris site gave:

jeff101 Lv 1

Sciren's initial post in this thread says "We started with a virtual screening of a massive library containing 36 billion compounds and narrowed it down to less than 900 candidates." Does this mean that there are less than 900 compounds that will give the +1000 Compound Library bonus in Puzzle 2476 (https://fold.it/puzzles/2013872)? Thanks.

Serca Lv 1

1) The ML277 molecule described in this article isn't the compound we start with in the puzzle.
2) When I tried to replicate ML277 in 2476, I received penalty points for TPSA and Rotatable bonds.
3) It seems that the compound we get at the start of the puzzle has some similarities with ML277. It should also fit well inside the same protein pocket. However, ML277's tolyl group points towards the middle of a long helix (S5) and interacts with PIP2 (critical for channel opening), whereas the starting compound we have seems to lack this ability. So, the starting compound doesn't seem to be able to activate this potassium channel. But it fits pretty well.

HuubR Lv 1

When I interpret @Sciren's blog post correctly, we are not supposed to use ML277, or even to imitate it too closely:

Since extensive research has been done to optimize ML277, we will be using some of these other candidates as starting molecules in this puzzle series to help broaden the search and development efforts.

I think it is up to our creativity to choose which parts of the molecule we like to keep, and which to change.
If and when the Compound Library should come back to life, we will then be able to see whether one or more of our compounds are actually among the (less than) 900 preselected ones.