In silico studies towards new BACE1 inhibitors

Beta-site APP-cleaving enzyme (BACE)1 is a type-1 membrane-anchored aspartyl protease playing an essential role in the release of Aβ peptides and Alzheimer’s Disease (AD) progression. Hence, the development of potent BACE1 inhibitors represents a logical approach for AD therapy development and it have been widely explored by the pharmaceutical industry worldwide.¹

Herein, we report the design of a virtual library of 300 compounds for in silico BACE1 inhibition assessment. These compounds were designed based on the hybridization of several hydrophobic fragments with aliphatic and aromatic amines, motifs identified in the literature by their ability to establish essential interactions with the amino acids present in the catalytic pocket of BACE1.

Affinity for BACE1 was measure through the binding energy estimation of the ligand-protein complex. Additionally, the compounds designed were assessed through the Lipinsky’s rule of 5 and additional attributes crucial for central nervous system (CNS) drugs were also considered.²

The most promising compounds will be synthesized through suitable and green N-alkylation techniques and their biological activity will be assessed in in vitro studies.

Acknowledgements: We thank the UID/Multi/04423/2019 through national funds provided by FCT-Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the program PT2020. This research was developed under Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds.