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

Abstract

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.

Keywords:

• Alzheimer
• BACE1 inhibitors
• molecular modeling

Acknowledgements

Grants from Universidad Nacional de San Luis (UNSL-Argentina) and Consejo Nacional de Investigaciones Cientifícas y Tećnicas (CONICET-Argentina) partially supported this work. This work was supported in part by a grant from ANPyCT, the Consejería de Economía, Innovación y Ciencia (Junta de Andalucía, Spain), and by Universidad de Jaén. This publication utilizes also research results of the CEBV project (ITMS 26240120034). Technical and human support provided by CICT of Universidad de Jaén (UJA, MINECO, Junta de Andalucía, FEDER) is gratefully acknowledged.