Dementia is a leading cause of death affecting more than 47.5 million people worldwide with additional 7.7 million new cases every year and expected to increase to 75.6 million by 2030. Alzheimer’s disease (AD) alone accounts for nearly 60-70 % cases of dementia. Other forms include vascular dementia, dementia with Lewy bodies (DLB) and frontotemporal dementia and Down syndrome (DS). Decrease in the activity of acetylcholine synthesizing enzyme has been observed with progression of these dementia disorders especially AD. Therefore, pharmacokinetically acceptable, water soluble, nonquaternary, irreversible inhibitors/ligands of ChAT could be developed as PET tracers and used to interrogate the cholinergic neurodegeneration observed in AD and other dementia disorders. In the present study a specific strategy is reported for the design of novel ChAT ligands based on Hologram Quantitative Structure Activity Relationship (HQSAR) and molecular docking analyses on a dataset of 26 ChAT inhibitors with reported IC<sub>50. </sub>The results provide insight into the contribution of specific structural moieties of the compounds towards their activity on ChAT, which allowed us to design novel ligands using lead optimization strategy implemented in Muse<sup>®</sup> Invent™ molecular design workflow. The novel findings may provide useful insights for the development of potential ChAT PET probes.

Hologram QSAR and structure-based design of novel small-molecule inhibitors of choline acetyltransferase

253rd National Meeting (2017)

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