title: Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization.
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.
authors: Center for Alzheimer Research, Karolinska Institutet; Department of Neurobiology, Care Sciences and Society; Division of Translational Alzheimer Neurobiology, NOVUM, 4th Floor, 141 86 Stockholm, Sweden.
authors: Rajnish
authors: R
authors: Kumar
authors: Department of Chemistry, Uppsala University, Uppsala, Sweden.
authors: Bengt
authors: B
authors: Långström
authors: Center for Alzheimer Research, Karolinska Institutet; Department of Neurobiology, Care Sciences and Society; Division of Translational Alzheimer Neurobiology, NOVUM, 4th Floor, 141 86 Stockholm, Sweden.
authors: Taher
authors: T
authors: Darreh-Shori
mesh_terms: D000465:Algorithms; D000544:Alzheimer Disease / Q000188:drug therapy; D020134:Catalytic Domain; D002795:Choline O-Acetyltransferase / Q000737:chemistry*; D002802:Cholinesterases / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D062105:Molecular Docking Simulation; D009281:Naphthalenes / Q000737:chemistry; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D008024:Ligands; D009281:Naphthalenes; D000644:Quaternary Ammonium Compounds; D011994:Recombinant Proteins; C055734:2-naphthoylethyltrimethylammonium; D002795:Choline O-Acetyltransferase; D002802:Cholinesterases