Exploring the binding of reversible covalent inhibitors of hCatL through computer simulation

The inhibition of Cathepsin L (hCatL) may be important to discovery of novel therapeutics against cancer and it's known that a halogen bonding interaction occur in the S3 pocket of this enzyme. Herein, we studied five nitrile-based inhibitors in a manner to explore the halogen bond of this compounds with hCatL. To explore the halogen bonding interaction we performed molecular dynamics simulations using an extra point (EP). To estimate the overall relative binding free energy we employed free energy perturbation (FEP). The results showed that EP usage improved the average of halogen bond and the use of FEP can predict the hCatL binding affinities of the compounds in study in close agreement with experimental results.