New substituted aminopyrimidine derivatives as BACE1 inhibitors: in silico design, synthesis and biological assays.
J Biomol Struct Dyn
; 37(1): 229-246, 2019 Jan.
Article
em En
| MEDLINE
| ID: mdl-29301478
We report in this work new substituted aminopyrimidine derivatives acting as inhibitors of the catalytic site of BACE1. These compounds were obtained from a molecular modeling study. The theoretical and experimental study reported here was carried out in several steps: docking analysis, Molecular Dynamics (MD) simulations, Quantum Theory Atom in Molecules (QTAIM) calculations, synthesis and bioassays and has allowed us to propose some compounds of this series as new inhibitors of the catalytic site of BACE1. The QTAIM study has allowed us to obtain an excellent correlation between the electronic densities and the experimental data of IC50. Also, using combined techniques (MD simulations and QTAIM calculations) enabled us to describe in detail the molecular interactions that stabilize the different L-R complexes. In addition, our results allowed us to determine what portion of these compounds should be changed in order to increase their affinity with the BACE1. Another interesting result is that a sort of synergism was observed when the effects of these new catalytic site inhibitors were combined with Ac-Tyr5-Pro6-Tyr7-Asp8-Ile9-Pro10-Leu11-NH2, which we have recently reported as a modulator of BACE1 acting on its exosite.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Ácido Aspártico Endopeptidases
/
Secretases da Proteína Precursora do Amiloide
Limite:
Humans
Idioma:
En
Revista:
J Biomol Struct Dyn
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Argentina
País de publicação:
Reino Unido