β-Secretase (BACE1) is an aspartate protease involved in the production of amyloid-β a major peptide responsible for the pathogenesis of Alzheimer’s disease. Given its role in the formation of amyloids leading to Alzheimer’s disease, it has been a major therapeutic target for intervention and has been a challenge in the past and the progress has been very slow. More than hundred crystal structures with inhibitors are available in the protein data bank. Many strategies for drug design have been employed in the design of numerous diverse ligands for this target and many have failed due to undesirable drug properties primarily the inability to cross the blood-brain barrier. In the present work we attempted to consider multiple crystal structures with bound inhibitors showing affinity in the range of 2–210 nM efficacy and optimize the pharmacophoric requirement based on the energy involved in binding termed as e-pharmacophore mapping. A high throughput screening combined with molecular docking, ADMET predictions, logP values and in vitro assay led to the identification of 7 potential compounds showing inhibition at 10µM which could be further developed as novel inhibitors for β-secretase.