Computational Inhibition Studies of the Human Proteasome by Argyrin‐Based Analogues with Subunit Specificity

A computational procedure was developed to study the subunit‐specific interactions of the proteasome inhibitors argyrin A and F, with the aim of indentifying the determinants of subunit selectivity. Three‐dimensional models of humanized proteasome active sites β 1 , β 2 and β 5 were developed and subsequently used in molecular docking simulations with the argyrin analogues. The subunit selectivity exhibited by each analogue could be explained based on the site‐specific interactions and a probability‐based specificity parameter derived in this study. A rational approach that involved maximizing site‐specific interactions was followed to guide the design of new argyrin analogues as specific inhibitors of the caspase‐like ( β 1 site) activity.