title: Computational inhibition studies of the human proteasome by argyrin-based analogues with subunit specificity.
abstract: 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.
authors: Department of Biological Sciences, University of Cyprus, Nicosia, 1678, Cyprus.
authors: Eriketi Z
authors: EZ
authors: Loizidou
authors: Constantinos D
authors: CD
authors: Zeinalipour-Yazdi
mesh_terms: D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
chemical_list: D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; D021122:Protein Subunits; C530877:argyrin A; C551982:argyrin F; D046988:Proteasome Endopeptidase Complex
keywords: 3D humanized proteasome models; argyin F; argyrin A; drug design; molecular modeling; proteasome inhibitors; subunit selectivity