The proteasome is the primaryATP-dependent, substrate-specific protein degradation pathway ineukaryotes. Inhibition of the active sites of the proteasome hasrecently shown promise in the treatment of multiple myeloma, andpotentially several other types of cancers. Along with the naturallyoccurring proteasome inhibitors syringolin A and glidobactin A,several novel syrbactin derivatives were investigated computationallyfor specificity to the proteasome chymotrypsin-like receptor.  Usingexisting crystal structures and the software package Autodock 4.2, acovalent docking method was employed for the unique,covalently-binding proteasome inhibitors. Supporting scripts, writtenin Python, were developed for automated preparation and analysis. TheAMBER package was used to model the dynamics of the complex obtainedfrom docking. The resulting trajectory data was analyzed usingMM/GBSA, and an energetic binding profile for the inhibitors wasobtained. A graphical Python script was developed to perform theMM/GBSA interaction energy calculations of the covalently-boundcomplexes.

Computational characterization of
proteasome inhibitors: Syringolin A, glidobactin A, and syrbactin
derivatives

241st National Meeting (2011)

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Computational characterization of proteasome inhibitors: Syringolin A, glidobactin A, and syrbactin derivatives