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J Biomol Struct Dyn. 2019 Jan;37(1):229-246. doi: 10.1080/07391102.2018.1424036. Epub 2018 Feb 1.

New substituted aminopyrimidine derivatives as BACE1 inhibitors: in silico design, synthesis and biological assays.

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a Facultad de Química, Bioquímica y Farmacia , Universidad Nacional de San Luis , Chacabuco 915, 5700 San Luis , Argentina.
b IMIBIO-CONICET, UNSL , Chacabuco 915, 5700 San Luis , Argentina.
c Departamento de Química , Universidad Nacional de Colombia , Ciudad Universitaria, Carrera 30, No. 45-03, Bogotá , Colombia.
d Departamento de Química Inorgánica y Orgánica , Universidad de Jaén , Campus Las Lagunillas s/n, 23071 Jaén , Spain.


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.


Alzheimer; BACE1 inhibitors; molecular modeling

[Indexed for MEDLINE]

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