An Integrated Molecular Approach to Predict Caffeine Analogs for Enhancing Cholinergic Signaling and Neuroprotection

OBIOL DIEGO; VIETRI AGUSTÍN; AMUNDARAIN MARÍA JULIA; ZAMARREÑO FERNANDO; COSTABEL MARCELO DANIEL; ANTOLLINI SILVIA SUSANA

Cordoba

Congreso; LI Reunion Anual Sociedad Argentina de Biofísica; 2023

Sociedad Argentina de Biofísica

In our study, we designed forty-one caffeine analogs with the aim of improving themodulation of acetylcholinesterase (AchE, PDBid: 4EY7) and activating the neuronalnicotinic acetylcholine receptor (α7-nAchR, PDBid: 7EKI) more effectively than theprototype caffeine. The central purpose of this work was to enhance cholinergicneurotransmission. Analogue T-44 emerged as the most promising due to its high affinityfor both targets. However, we expanded our analysis to assess the impact of all designedanalogs on two other molecular targets: the muscle nicotinic acetylcholine receptor(PDBid: 7QL5) and the human adenosine receptor (hA2AR, PDBid: 3RFM), a G proteincoupled receptor, class A. Inhibition of hA2AR by caffeine could also offer potentialbenefits in terms of neuroprotection.We conducted a thorough analysis of the pharmacokinetic and molecular properties ofeach analog and performed molecular docking at the orthosteric sites of the targets todetermine the binding affinity score. For the prediction of pharmacokinetic parameters,we used pkCSM and SwissADME, and for performing molecular docking, we employedAutoDock Vina. We compared these results with known compounds to identify potentialcandidates with a high potential to modulate the activity of multiple target moleculessimultaneously.Our findings reveal that some analogs, in addition to the prominent T-44, emerge aspotential candidates to enhance cholinergic activity and potentially provideneuroprotection. In future studies, we plan to carry out molecular dynamics simulationsand in vitro analyses to confirm the effects of these analogs on molecular targets.This work presents qualitative structure-activity relationship studies that provide relevantinformation for the design of new molecules that could enhance neurotransmission andneuroprotection.