Tuning and predicting biological affinity: aryl nitriles as cysteine protease inhibitorsDedicated to Professor Wilfred van Gunsteren on the occasion of his 65th birthday.This article is part of the Organic & Biomolecular Chemistry 10th Anniversary issue.Electronic supplementary information (ESI) available: Detailed experimental procedures and spectroscopic data for all compounds, biological assays and additional figures and tables. See DOI: 10.1039/c2ob00034b

A series of aryl nitrile-based ligands were prepared to investigate the effect of their electrophilicity on the affinity against the cysteine proteases rhodesain and human cathepsin L. Density functional theory calculations provided relative reactivities of the nitriles, enabling prediction of their biological affinity and cytotoxicity and a clear structure-activity relationship. The influence of the electrophilicity of aromatic nitriles on cysteine protease inhibition and cytotoxicity was investigated. Calculations were used to obtain nitrile electrophilicities, revealing a clear correlation with biological affinity.