title: Identification of sumoylation inhibitors targeting a predicted pocket in Ubc9.
abstract: 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.
authors.affiliation: Structural Bioinformatics Team, Division of Structural and Synthetic Biology, Center for Life Science Technologies, RIKEN , 1-7-22 Suehiro, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Mikako
authors.initials: M
authors.lastname: Hirohama
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D001681:Biological Assay; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D058207:Sumoylation / Q000187:drug effects; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014584:User-Computer Interface; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D008024:Ligands; C092317:RANGAP1 protein, human; D054852:Small Molecule Libraries; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9