Our cheminformatics team has developed a new Screening Library targeting ATP-sensitive potassium (KATP) channels and specifically focusing on the Kir6.1/SUR2B subunits. This original Library, currently comprising over 1,100 drug-like screening compounds, is designed to become a highly efficient tool for the discovery of selective Kir6.1/SUR2B inhibitors that can potentially lead to novel therapeutic approaches to cardiovascular diseases.
The compound selection can be customized based on your requirements, cherry picking is available.
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Background information
ATP-sensitive potassium (KATP) channels are essential for linking cellular metabolism to membrane excitability, playing a critical role in various physiological processes. These channels are hetero-octameric complexes composed of four pore-forming subunits from the inwardly rectifying potassium (Kir) channel family (Kir6.1 or Kir6.2) and four regulatory subunits from the sulfonylurea receptor (SUR) family (SUR1, SUR2A, or SUR2B) [1].
Such ion channels are found in many tissues, including pancreatic β-cells, heart, skeletal muscle, vascular smooth muscle, and brain, where they couple the cell’s metabolic state to its membrane potential. The specific combination of Kir6.x and SURx subunits determines the unique electrophysiological and pharmacological properties of each KATP channel subtype.
Kir6.1 and SUR2B are particularly important in the smooth muscle cells of blood vessels, where they regulate vascular tone, blood flow, and blood pressure [2]. This makes Kir6.1/SUR2B a promising target for cardiovascular disease therapies. However, developing selective inhibitors for Kir6.1/SUR2B without affecting Kir6.2/SUR1 channels has been challenging. Recent studies identified N-aryl-N'-benzylurea (VU0542270) as a selective inhibitor of Kir6.1/SUR2B, with no apparent activity against Kir6.2/SUR1 or other Kir channels [3].
Compound selection
This Screening Set comprises over 1,100 predicted selective inhibitors of Kir6.1/SUR2B, picked out using available data for reported selective inhibitors as a reference, as well as molecular docking against our in-house HTS Compound Collection. According to the docking results, all compounds presented in the Library are potentially inactive on Kir6.2/SUR1.
Key features:
- Method: glide ligand docking (standard precision)
- X-Ray data used: 7MIT
- Constraints: H-bond (Tyr1205)
- Filters used: no
- Number of compounds selected: 1,123
Fig. 1. Lead compound (F0723-0020) in the binding site of the Kir6.1/SUR2B complex. The complex has been obtained by means of molecular docking.
Representative screening compounds from the Kir6.1/SUR2B Targeted Screening Library
Reference:
- Driggers CM, Shyng SL. Mechanistic insights on KATP channel regulation from cryo-EM structures. J Gen Physiol. 2023;155(1):e202113046. doi:10.1085/jgp.202113046
- McClenaghan C, Nichols CG. Kir6.1 and SUR2B in Cantú syndrome. Am J Physiol Cell Physiol. 2022;323(3):C920-C935. doi:10.1152/ajpcell.00154.2022
- Li K, McClenahan SJ, Han C, et al. Discovery and Characterization of VU0542270, the First Selective Inhibitor of Vascular Kir6.1/SUR2B KATP Channels. Mol Pharmacol. 2024;105(3):202-212. Published 2024 Feb 15. doi:10.1124/molpharm.123.000783