Search of new inhibitors of BACE1. An experimental and theoretical study

GUTIERREZ, LUCAS; SANCHEZ, EMILSE ; VETTORAZZI, MARCELA; COBOS, JUSTO ; ENRIZ RICARDO

Santiago del Estero

Congreso; Sociedad Argentina de Biofísica Reunión Anual SAB 2015; 2015

Sociedad Argentina de Biofísica Reunión Anual SAB 2015

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. In the search for new inhibitors of the catalytic site of BACE1, we take as starting structure compounds 1 and 2, which have been previously reported by Gravenfor [1]. From a molecular modeling study, by using combined molecular dynamics simulations and quantum calculations, we designed a new series of pyrimidine derivatives. These compounds exhibited significant inhibitory activity in the catalytic site of BACE1. Our molecular modeling studies suggest that the main interactions that stabilize these molecular complexes are those pyrimidine compounds with amino acids set Asp32, Asp228 and Thr231.On the other hands, we have recently reported a new series of peptides with inhibitory properties on the exosite of the enzyme BACE1 [2]. Among these peptides, Ac-Tyr5-Pro6-Tyr7-Asp8-Ile9-Pro10-Leu11-NH2 showed the largest inhibitory activity. Based on these results it was evaluated a possible synergistic effect between this peptide and pyrimidine derivatives. As a very interesting result, we found that there is some synergy between these two compounds, which makes these compounds as excellent candidates for further study and new developments.