INVESTIGADORES
VEGA HISSI Esteban Gabriel
congresos y reuniones científicas
Título:
Molecular insight into the interaction mechanisms of Amino-2H-imidazole derivatives with BACE1 protease. A QM/MM and QTAIM study
Autor/es:
ESTEBAN G. VEGA HISSI; RODRIGO TOSSO; DANIEL RICARDO ENRIZ; LUCAS JOEL GUTIERREZ
Lugar:
Santiago de Chile
Reunión:
Congreso; 10th Congress of the World Association of Theoretical and Computational Chemists (WATOC 2014); 2014
Institución organizadora:
WATOC
Resumen:
β-secretase or β-site amyloid precursor protein cleaving enzyme (BACE-1) has been considered as a striking therapeutic target for Alzheimer?s disease (AD) treatment and several attempts have been focused on the development of inhibitors of this key enzyme. Recently, two new amino-2H-imidazole compounds, (R)-1t and (S)-1m, with a very interesting inhibitory profile have been synthesized and co-crystallized within the enzyme active site [1]. In this study, we described quantitatively the interactions between these inhibitors and BACE-1 from a theoretical point of view. We employed a hybrid Quantum Mechanics-Molecular Mechanical (QM/MM) method together with a QTAIM (Quantum Theory of Atoms In Molecules) analysis to investigate in details the binding of this class of inhibitors to BACE-1. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino-2H-imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions of the inhibitors within the enzyme were stronger when they present a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5-dimethyl-4-methoxyphenyl group of compound (S)-1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)-1t is bound to the enzyme. The presence of a second, lipophilic substituent conferred certain additional stability, especially in compound (R)-1t, but became a compromise between permeability and collateral hErg affinity. These results also showed that from relatively simple molecular modeling techniques it is possible to explain the behavior of inhibitors that have a similar affinity for the enzyme. In this sense it is important to point out the accuracy of the combined ONIOM - QTAIM analysis that allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.