Due ti its involvement in many cellular pathways, the human proteasome has been a popular target for drug discovery. Inhibitors of the proteasome have to be highly specific and inhibit only one of proteasome's activities in order to minimize toxic effects and maximize therapeutic potential. In this study, we developed a computational methodology to guide the design of proteasome inhibitors with subunit specificity. The naturally occuring proteasome inhibitor, argyrin A, that targets active sites �1, �2 and �5, served as the starting point upon which the new analogues were designed. Using the crystal structure of the yeast proteasome we developed humanized models and analyzed the binding conformations of argyrin A to the �1, �2 and �5 sites by molecular docking simulations. The subunit selectivity was determined by analysis of the binding conformations and site interactions of argyrin A and analogues. Predictions for selective binding distributions for �1, �2, and �5, were derived based on the relative binding affinity of each analogue towards argyrin A. Two new analogues were identified as promising �1 and one as �5 selective inhibitors. The computational protocol that was developed in this study may have a significant impact on the field of drug design when subunit selectivity of inhibitors is desirable. 

Design of argyrin analogs as proteasome inhibitors with subunit specificity

247th National Meeting (2014)

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