Sumoylation is a post-translational modification that plays an important role in 
a wide range of cellular processes. Among the proteins involved in the 
sumoylation pathway, Ubc9 is the sole E2-conjugating enzyme required for 
sumoylation and plays a central role by interacting with almost all of the 
partners required for sumoylation. Ubc9 has been implicated in a variety of 
human malignancies. In order to exploit the therapeutic potential of Ubc9, we 
have identified the potential site to target for rational drug design using 
molecular modeling approaches. The structural information derived was then used 
to prioritize hits from a small-molecule library for biological assay using a 
virtual screening protocol that involves shape matching with a known inhibitor 
inhibitors and docking of a small-molecule library utilizing computational 
approaches that incorporate both ligand and protein flexibility. Nineteen 
compounds were acquired from different chemical vendors and were tested for Ubc9 
inhibitory activity. Five compounds showed inhibitory activity against Ubc9, out 
of which one compound was selected for further optimization. A similarity search 
was then carried out to retrieve commercially available derivatives, which were 
further acquired and assayed, resulting in two compounds with acceptable 
potency. These two compounds can be used as starting points for the development 
of more potent inhibitors of Ubc9 targeting the predicted site.