Structure and Ligand Based Rational Drug Design for Bace-1 Inhibitors

E. P.      Semighini; Carlton      A. Taft; C. H. T. P.      Silva

Abstract

Alzheimer’s Disease (AD) is the major cause of senile dementia, flawing out 10% of 65 years old population and 50% of 85 years old, globally. The major physiopathology of AD is the deposition of extracellular neuritic plaques in memory related areas of the brain. These plaques are composed of the β-amyloid peptide resulting from the amyloidogenic pathway, that starts with the β-secretase enzyme. BACE-1 (β-secretase 1) is considered one of the most promising treatments of the disease. In this work, different molecular modeling and drug design techniques were used to design novel inhibitors of BACE-1, starting from structures available in the Protein Data Bank. The results obtained from virtual screening of compound libraries lead to 28 promising compounds, which were then evaluated by toxicity prediction, pharmacokinetic properties and analysis of the binding modes in the catalytic site, resulting in 10 compounds with high theoretical inhibition potential.

Keywords: BACE-1, Alzheimer, virtual screening