Potency prediction of β-secretase (BACE-1) inhibitors using density functional methods.

Scoring potency is a main challenge for structure based drug design. Inductive effects of subtle variations in the ligand are not possible to accurately predict by classical computational chemistry methods. In this study, the problem of predicting potency of ligands with electronic variations participating in key interactions with the protein was addressed. The potency was predicted for a large set of cyclic amidine and guanidine cores extracted from β-secretase (BACE-1) inhibitors. All cores were of similar size and had equal interaction motifs but were diverse with respect to electronic substitutions. A density functional theory approach, in combination with a representation of the active site of a protein using only key residues, was shown to be predictive. This computational approach was used to guide and support drug design, within the time frame of a normal drug discovery design cycle.