Uncovering false positives on a virtual screening search for cruzain inhibitors

Some unexpected promiscuous inhibitors were observed in a virtual screening protocol applied to select cruzain inhibitors from the ZINC database. Physical–chemical and pharmacophore model filters were used to reduce the database size. The selected compounds were docked into the cruzain active site. Six hit compounds were tested as inhibitors. Although the compounds were designed to be nucleophilically attacked by the catalytic cysteine of cruzain, three of them showed typical promiscuous behavior, revealing that false positives are a prevalent concern in VS programs.

Graphical abstractPromiscuous inhibition of cruzain is reported for three out of six virtual screening selected compounds. The promiscuous mechanism was assumed after the recovery of the enzyme activity following the addition of 0.1% Triton.Figure optionsDownload full-size imageDownload as PowerPoint slide