In silico studies of a caffeine analog on AchE and α7-nAchR

DIEGO OBIOL; JUAN PABLO MUNAFÓ ; AGUSTÍN VIETRI; MARÍA JULIA AMUNDARAIN; OMAR JAURE; FERNANDO ZAMARREÑO; SILVIA ANTOLLINI; MARCELO D. COSTABEL

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

We designed forty caffeine analogues with the aim of obtaining one capable of inhibitingacetylcholinesterase (AchE) and activating the neuronal nicotinic acetylcholine receptor(α7-nAchR) with greater potency than the prototype molecule. The main purpose is toincrease Ach at the synaptic junction. AchE (pdb: 4EY7) and α7-nAchR (7EKI) receptorswere modeled. The QMEANDisCo scores of each model are similar to the initial targets, butboth with an improved Ramachandran plot. The binding affinity to both targets was thenevaluated with each of the designed molecules by molecular docking and the analogueT-44 emerged prima facie as the most intriguing due to its binding affinity to both targets.Therefore, the molecular dynamics of the ligand with each of the targets was performed.The runs were prolonged as long as necessary until convergence of both target andligand. The target molecules remain stable over the simulated time, while T-44 examinesseveral possible positions in α7-nAchR. The most representative positions of the ligandwere recovered, and the interactions established between each target and its ligand wereanalyzed at that position. The ligand has a preference for amino acids (AA) of theperipheral anionic site (PAS) of the enzyme, while the ligand establishes contacts almostexclusively with AA that constitute the hydrophilic pocket at the orthosteric site of thereceptor. In both situations, the formation of hydrogen bonds is highlighted. We proposethe synthesis of this very interesting new compound as an enhancer of the cholinergicsignal for perform electrophysiological analyses to confirm its possible effects onmolecular targets. The preference of T-44 for ASP-74, AA which modulates theconformation of both the PAS and the active site of the enzyme, could explain its AChEinhibitor effect. In addition, it would be interesting to evaluate how it modulates theorthosteric site of the receptor.