Structural analysis, simulation, and molecular docking of aza-nitrile into cathepsins to explain the high selectivity

The potencies of aza-nitriles toward cathepsin K have been well explained using the molecular docking program GOLD 5.1. However, this is insufficient to explain the selectivity of these inhibitors for cathepsin K over cathepsins L, S and B. In this study, the optimal binding models of aza-nitriles in cathepsins were constructed through structure optimization and reasonable dislodging of unfavorable binding configurations. The spatial structures of aza-nitriles were analyzed through 1H–1H COSY and 1H–1H NOESY, as well as through basic analysis of 1H NMR, 13C NMR and HPLC-MS (ESI) as reported in previous studies. All docking results were subsequently screened and any warped and/or seriously incompatible models were removed by scoring (high to low) until the most suitable docking mode with proper configuration and a high score was found, which was used for further analysis. The final results exhibited Goldscore fitness ratios that correlate well with the known selectivities of aza-nitriles for cathepsin K over cathepsins L, S. Such improvements would be useful to predict more selective inhibitors in drug development.