Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 31247Article in journal (Refereed) Published
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 alpha-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 similar to 88 nM). In contrast, alpha-NETA exhibited an IC50 of -30 mu M 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.
Place, publisher, year, edition, pages
2016. Vol. 6, 31247
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-302677DOI: 10.1038/srep31247ISI: 000381130900001PubMedID: 27507101OAI: oai:DiVA.org:uu-302677DiVA: diva2:967476
FunderThe Karolinska Institutet's Research FoundationStiftelsen Olle Engkvist ByggmästareÅke Wiberg FoundationMagnus Bergvall FoundationThe Dementia Association - The National Association for the Rights of the DementedStiftelsen Gamla Tjänarinnor