Discovery and characterization of novel pyridone and furan substituted ligands of choline acetyltransferase.

Baidya AT, Dante D, Das B, Wang L, Darreh-Shori T, Kumar R

Eur J Pharmacol 998 (-) 177638 [2025-07-05; online 2025-04-17]

The key to the management of two devastating diseases, namely Alzheimer's Disease (AD) and Amyotrophic Lateral Sclerosis (ALS) lies in an early diagnosis, which is difficult due to its multifactorial nature. However, a common hallmark of AD and ALS is degeneration of cholinergic system. Choline acetyltransferase (ChAT) has been proposed as a potential target for development of cholinergic-specific biomarker. However, lack of selective, potent, brain permeable molecular probes of ChAT hinder development of ChAT biomarkers. In this study, we have successfully utilised structure-based virtual screening approach and identified two ChAT inhibitors from a database of 1.4 million compounds. The compounds were then subjected to rigorous in vitro characterization. Compound V6 showed Ki value of 11 μM and IC50 value of 21.73 μM, while V15 showed Ki and IC50 values of 4.5 and 9.42 μM, respectively for ChAT enzyme. V6 and V15 showed good solubility of 0.21 mg/mL and 0.17 mg/mL respectively and cytotoxicity analysis indicated no toxicity. We also performed a 200 ns molecular dynamics simulation, which revealed the intricate interaction dynamics for V6 and V15 with ChAT binding pocket. Moreover, the Tanimoto similarity analysis indicated the novelty and structural diversity of the hits. In conclusion, these validated hits provide a platform to develop potent, selective, blood-brain barrier permeable small molecules as chemical probes of ChAT or as Positron Emission Tomography tracer for early diagnosis and/or in vivo monitoring of the effect of new therapeutic candidates in spectrum of neurodegenerative disorders, in which cholinergic deficit is one of the hallmarks.

Bioinformatics Support for Computational Resources [Service]

PubMed 40252901

DOI 10.1016/j.ejphar.2025.177638

Crossref 10.1016/j.ejphar.2025.177638

pii: S0014-2999(25)00392-9