QTAIM calculations to evaluate the molecular interaction in acetyl and butyrylcholinesterase complexed with pyrrolo[2,1-a]isoquinolin-3-ones

PARRAVICINI, OSCAR; ANGELINA, EMILIO; GARRO, ADRIANA; GARIBOTTO, FRANCISCO; VETTORAZZI, MARCELA; CABEDO, NURIA; ENRIZ, DANIEL

Congreso; Primeras jornadas virtuales de la Sociedad Argentina de Biofísica; 2020

SAB

We have previously demonstrated that QTAIM calculations are a useful tool to evaluate the molecular interactions that stabilize ligand-receptor complexes (1). Based on these results and in order to better understand the interactions involved in different acetyl (AChE) and butyryl (BChE) cholinesterase complexes, we conducted a QTAIM study for a series of substituted pyrrolo[2,1-a]isoquinolinones. Some of them, bearing a carbamate moiety, have a slight structural resemblance to the cholinesterase inhibitor rivastigmine.Regarding AChE, our calculations showed that the activity of these carbamates seems to be conditioned to their ability to reach the catalytic anionic site (CAS). Thus, active compounds are either anchored to CAS or simultaneously anchored to CAS and the peripheral anionic site (PAS). Binding of these compounds resembles that of acetylcholine: the carbonyl oxygen atom points toward the oxyanion hole and the activated carbon atom is properly positioned for nucleophilic attack by the Ser200 residue, which plays a key role for AChE inhibition. In addition, the 01D 6FE -lactam ring of these derivatives is stacked on top of Trp84 and several C?H···π interactions with the Trp233, Phe288 and Phe290 residues contribute to stabilize the complexes. On thecontrary, the lack of activity of compounds with bulky substituents, as in the case of the 8,9-ditethylcarbamate derivative, could be explained as they are almost completely bound to PAS.Although the structures of AChE and BChE are similar, their residue sequences show slight differences. Thus, larger ligands are allowed to access the CAS in BChE, compared to AChE. Our results suggest that the 8,9-ditethylcarbamate derivative, the only one showing selective inhibitory activity against BChE, is anchored at the CAS of BChE.However, its weaker inhibitory effect compared to rivastigmine could be explained since its hydrolysable carbamate moiety is not properly placed for nucleophilic attack by the reactive serine in BChE.