Alzheimer's disease (AD), impacting 55 million globally, is an incurable neurodegenerative condition. Early synaptic loss in the forebrain cholinergic system prompted the development of acetylcholinesterase inhibitors (AChE-Is) as a primary dementia treatment. However, their dose-limiting toxicities, tied to cholinergic actions, limit their efficacy to modest symptomatic improvements, hampering potential disease-modifying effects.

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As AChE levels decline in AD-affected brain regions, the therapeutic value diminishes. Recent research suggests that selectively inhibiting butyrylcholinesterase (BChE), elevated in AD, enhances acetylcholine and cognition without the undesirable effects of AChE-Is. BChE inhibition offers an innovative AD treatment, especially in the late stage of the disease.

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In our ongoing efforts, we employed a structural-based virtual screening approach using a database of 1.2 million compounds from MolPort and Interbioscreen. This led to the discovery of two promising BChE inhibitors, PE01 and PE02, displaying potent and selective activity with unique structures and CNS delivery potential.

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Using advanced computational methods like similarity-based approaches, we further screened 35 million molecules identifying 18 potential potent, selective, and brain-specific BChE inhibitors. This computational optimization approach, based on the previously discovered two lead compounds, sets the stage for further experimental investigations.