Alzheimer’s Disease (AD) is a serious neurodegenerative condition impacting nearly 5.8 million people over 65 years old in the United States. This year alone, the National Institute of Health budgeted $3.2 billion for Alzheimer’s research to help develop safe and effective treatments. Currently available therapeutic options are limited, and the known drugs work by slowing down the disease progression as opposed to treating the disease. The purinergic signaling system displays early regulation of outcomes related to Alzheimer’s disease through the control of microglia and astrocytes. While purinergic receptors are critical in modulating the neuroinflammation accompanying AD onset and progression, they are largely unexplored as potential targets for AD drug discovery. We have collected, curated, and integrated the largest publicly available chemical bioactivity data from ChEMBL and PubChem for eight purinoceptors known to regulate microglial control of inflammation, synaptic remodeling and pruning and debris clearing, as well as astrocytic scar formation and inflammation. We have developed Quantitative Structure-Activity Relationship (QSAR) models using decision tree ensembles and various chemical descriptors. The best validated models showed external predictive accuracy in the range of 0.79- 0.82 CCR.   These models were employed for virtual screening against the Enamine Diverse REAL drug-like compounds library (25M non-toxic compounds) filtered for blood-brain barrier permeability. For targets with experimentally determined three-dimensional structure but insufficient historical data on compound bioactivity to contemplate QSAR modeling, we employed molecular docking and similarity searches. Similar techniques were used to elucidate the binding mechanism of top VS hits for targets with sufficient data.  The top computational hits are awaiting experimental confirmation, which may result in the discovery of potential novel therapeutics to treat AD.

Cheminformatics-driven discovery of microglia and astrocyte modulators as potential agents to treat Alzheimer’s disease

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.