Nicotinic acetylcholine receptors (nAChRs) are cylindrically shaped receptors that form ligand-gated (or chemically controlled) ion channels throughout the central, sympathetic, and parasympathetic nervous systems. These receptors are crucial protein targets for various neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, Tourette's syndrome, schizophrenia, depression, anxiety, nicotine addiction, and stress disorders.
Our cheminformatics team presents a new targeted Screening Set containing over 900 drug-like screening compounds. As predicted by molecular docking, these novel molecules can exhibit nicotinic acetylcholine receptor inhibitory activity.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background information
The key function of nicotinic acetylcholine receptors is triggering rapid neuromuscular and neural transmissions [1]. The formation of different heteromeric and homomeric nAChR subtypes with a combination of its subunits, such as α1–α7, α9, α10, β1–αβ4, γ, δ, and ε (in mammals), imparts specific kinetic and pharmacological properties to each subtype[2]. Among them, the heteromeric α4β2 subtype is one of the most widespread in the brain. It is known to be responsible for mood, reward, cognition, and nociception [3], thus demonstrating the influence of nAChRs on numerous physiological and behavioral processes.
Compound selection
Potential binding sites on the surface of a nicotinic receptor (PDB ID: 6CNJ) were predicted. Site 5 (SiteScore = 1.080) was selected for a standard precision ligand docking against the Life Chemicals HTS Compound Collection (Figure 1). The site was chosen based on the amino acid residues of the ligand binding site [5].
As a result, over 900 top-scored screening compounds were selected for this nAChR Targeted Screening Set. All presented compounds correspond to QikProp parameters and descriptors and have a docking score value less than -10.
![Nicotinic receptor binding site for the docking. The amino acid residues of the binding site with the ligand are marked in red and purple [#], with Neuronal acetylcholine receptor subunit alpha-4 and Neuronal acetylcholine receptor subunit beta-2 marked in green and yellow, respectively. The selected site is located between E and D chains.](img/library_descriptions/Nicotinic%20Acetylcholine%20Receptor%20Targeted%20Library/Nicotinic_Acetylcholine_Receptor_Targeted_Library_1.png "Nicotinic receptor binding site for the docking. The amino acid residues of the binding site with the ligand are marked in red and purple [#], with Neuronal acetylcholine receptor subunit alpha-4 and Neuronal acetylcholine receptor subunit beta-2 marked in green and yellow, respectively. The selected site is located between E and D chains.")
Figure 1. Nicotinic receptor binding site for the docking.
The amino acid residues of the binding site with the ligand are marked in red and purple [#], with Neuronal acetylcholine receptor subunit alpha-4 and Neuronal acetylcholine receptor subunit beta-2 marked in green and yellow, respectively. The selected site is located between E and D chains.
Fig. 2. Spatial structure binding site of the complex of the nicotinic receptor with lead docking molecule F6571-0715 (docking score = -12.75).
Representative screening compounds from the Nicotinic Acetylcholine Receptor Screening Library
Reference:
- Jiménez-Pompa, A.; Albillos, A. Nicotinic Receptors in Human Chromaffin Cells: Characterization, Functional and Physical Interactions between Subtypes and Regulation. Int. J. Mol. Sci. 2024, 25, 2304. https://doi.org/10.3390/ijms25042304
- Crestini, A.; Carbone, E.; Rivabene, R.; Ancidoni, A.; Rosa, P.; Tata, A.M.; Fabrizi, E.; Locuratolo, N.; Vanacore, N.; Lacorte, E.; et al. A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia. Cells 2024, 13, 237. https://doi.org/10.3390/cells13030237.
- Hilscher Markus M.; Mikulovic S.; Perry S.; Lundberg S.; Kullander K. The alpha2 nicotinic acetylcholine receptor a subunit with unique and selective expression in inhibitory interneurons associated with principal cells. Pharmacological Research. 2023, vol. 196, https://doi.org/10.1016/j.phrs.2023.106895.
- Terry A.; Jones K.; Bertrand D. Nicotinic acetylcholine receptors in neurological and psychiatric diseases.Pharmacological Research, vol. 191, 2023, https://doi.org/10.1016/j.phrs.2023.106764.
- Walsh RM Jr, Roh SH, Gharpure A, Morales-Perez CL, Teng J, Hibbs RE. Structural principles of distinct assemblies of the human α4β2 nicotinic receptor. Nature. 2018;557(7704):261-265. doi:10.1038/s41586-018-0081-7.