Abstract
Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of α-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, α-NETA exhibited an IC50 of ~30 μM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer’s disease.
Highlights
Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway
We confirmed the activity of α-NETA, the only commercially available Choline acetyltransferase (ChAT) inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM)
Statistical Hologram Quantitative Structure Activity Relationship (HQSAR) models were prepared by using various components such as atoms (A), bonds (B), connections (C), hydrogens (D), chirality (Ch), donor-acceptor (DA)
Summary
Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Histopathological analyses show 75–98% reduced levels of ChAT in brain regions that become affected early and severely in dementia[6,7], such as the regions of medial temporal lobe[8], involved in memory consolidation This leads to the use of cholinesterase inhibitors with the rational of prolonging the action of ACh at the downstream targets of the remaining cholinergic projections. An unmet need in the dementia field is the lack of a biomarker addressing the health of CNS, in particular of the cholinergic neuronal projections In this context, in vivo brain imaging by positron emission tomography (PET) with specific tracers are gaining important clinical applications and is already proven to be invaluable www.nature.com/scientificreports/. There are currently several tracers under development that are targeting pathological aggregates of tau protein, which is another key feature of the AD brain
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