In silico exploration of cholinergic activity and neuroprotection of novel caffeine analogues

Alzheimer's disease (AD) is characterized by a cholinergic deficit, prompting conventional therapies to elevate acetylcholine levels as a compensatory measure. Two main strategies involve the inhibition of acetylcholinesterase (AChE) and/or the stimulation of acetylcholine receptors (AChR). Caffeine (CFF), known as a partial agonist of nAChR and an AChE inhibitor, acts as a cholinergic enhancer. Additionally, it is suggested that CFF may exhibit neuroprotective capabilities through the inhibition of the human adenosine receptor type 2A (hA2AR) in the brain's striatum, potentially preventing cellular apoptosis. This study explores on the design and prediction of the bioactivity of CFF analogues with the aim of enhancing cholinergic signaling and providing neuroprotection to improve their therapeutic potential. We employed tools to predict pharmacokinetic and bioactivity properties, molecular docking, molecular dynamics, and target prediction to identify potential candidates among the designed CFF analogues capable of enhancing neurotransmission and providing cellular protection. In a novel approach, a normalized index is proposed for the combined analysis of the pharmacokinetic parameters and molecular docking binding affinities, which facilitates the systematic evaluation and comparison of the synthesized analogues and minimizes subjectivity in the selection of promising candidates. Results indicated that some analogues show promise in improving cholinergic activity and providing neuroprotection. These findings instill optimism, encouraging further research to corroborate their effects, while also representing a significant step towards the development of new therapeutic agents for AD.