Computer Modeling Study of Small Molecule Inhibitors of Ubiquitin-activating Enzyme (El)

Ubiquitination plays a critical role in signal transduction, DNA repair, and regulation of cell activities. Alterations in the ubiquitination process are found in the majority of tumors. Therefore, the ubiquitination system is a new promising target for cancer treatment. A number of small molecules that inhibit El have been found. To understand how the inhibitors work and therefore design more potent and specific inhibitors, we have used molecular modeling techniques to investigate the binding modes of these inhibitors. The preliminary results of our study demonstrated that these inhibitors bind to the large, central cleft in the middle of the El protein, near the active site cysteine. Our study will be of help to identify the pharmacophores of these inhibitors binding to human El and design new pharmaceuticals for the treatment of human cancer.