One of the two biomolecular targets presented in the 2018 D3R Grand Challenge 4 (GC4) was BACE-1 (β -amyloid precursor protein cleaving enzyme 1). It is a transmembrane aspartyl protease and generates β -amyloid peptide by cleaving the amyloid precursor protein. β -amyloid peptides are involved in Alzheimer's Disease (AD) , and BACE-1 has been seen as a possible target for the treatment and prevention of AD. Fig. shows the binding site of BACE-1 characterized by the aspartyl dyad formed by the residues Asp32 and Asp228, which acts respectively as the acid and base during the proteolysis reaction .