Ligand and Structure-Based Drug Design as Strategies for the Screening of New BACE1 Inhibitor Candidates

The neurogeneration observed in Alzheimer's disease (AD) is due to the formation of two abnormal structures in the brain of patients with this disease, i.e. neurofibrillary tangles and amyloid plaques. The amyloid plaques are formed by fragments of insoluble beta-amyloid peptides generated by cleaving the amyloid precursor protein (APP) by the beta-secretase enzyme (BACE 1). To date there are no marketed drugs that can stop or slow the progress of AD making it necessary for drug design research in this area, to be undertaken, BACE1 have presented as a major target for delaying the symptoms of AD, since it would prevent inhibition of the formation of insoluble fragments of beta-amyloid protein, and therefore the formation of amyloid plaques. The present study is aimed at screening millions of chemical compounds with pharmaceutical characteristics present in commercial databases, using virtual screening techniques to identify compounds that would inhibit BACE1. Two strategies have been proposed for this: (i) similarity virtual screening followed by docking and (ii) a pharmacophore approach followed by similarity virtual screening. After filtering the compounds, pharmacokinetic and toxicity properties were predicted. Finally two compounds one from each strategy was selected, which could eventually lead to in vitro studies of biological activity.