IMASL   20939
INSTITUTO DE MATEMATICA APLICADA DE SAN LUIS "PROF. EZIO MARCHI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
QTAIM calculations to evaluate the molecular interaction in acetyl and butyrylcholinesterase complexed with pyrrolo[2,1-a]isoquinolin-3-ones
Autor/es:
GARRO, ADRIANA; CABEDO, NURIA; PARRAVICINI, OSCAR; GARIBOTTO, FRANCISCO; ENRIZ, RICARDO DANIEL; ANGELINA, EMILIO; VETTORAZZI, MARCELA
Lugar:
modalidad virtual
Reunión:
Congreso; Biofísica en tiempos de COVID-19 SAB 2020; 2020
Institución organizadora:
Sociedad Argentina de Biofísica
Resumen:
We have previously demonstrated that QTAIM calculations are a useful tool to evaluatethe molecular interactions that stabilize ligand-receptor complexes (1). Based on theseresults and in order to better understand the interactions involved in different acetyl(AChE) and butyryl (BChE) cholinesterase complexes, we conducted a QTAIM study for aseries of substituted pyrrolo[2,1-a]isoquinolinones. Some of them, bearing a carbamatemoiety, have a slight structural resemblance to the cholinesterase inhibitor rivastigmine.Regarding AChE, our calculations showed that the activity of these carbamates seems tobe conditioned to their ability to reach the catalytic anionic site (CAS). Thus, activecompounds are either anchored to CAS or simultaneously anchored to CAS and theperipheral anionic site (PAS). Binding of these compounds resembles that ofacetylcholine: the carbonyl oxygen atom points toward the oxyanion hole and theactivated carbon atom is properly positioned for nucleophilic attack by the Ser200residue, which plays a key role for AChE inhibition. In addition, the 01D6FE -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 the8,9-ditethylcarbamate derivative, could be explained as they are almost completelybound to PAS.Although the structures of AChE and BChE are similar, their residue sequences showslight differences. Thus, larger ligands are allowed to access the CAS in BChE, comparedto AChE. Our results suggest that the 8,9-ditethylcarbamate derivative, the only oneshowing selective inhibitory activity against BChE, is anchored at the CAS of BChE.However, its weaker inhibitory effect compared to rivastigmine could be explained sinceits hydrolysable carbamate moiety is not properly placed for nucleophilic attack by thereactive serine in BChE.