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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 β1, β2 and β5 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 (β1 site) activity.