Skip to main content
  • Poster presentation
  • Open access
  • Published:

Identification of SUMO activating enzyme 1 inhibitors utilizing virtual screening approach

Sumoylation is a post-translational modification affecting diverse cellular processes including DNA replication and repair, chromosome packing and dynamics, genome integrity, nuclear transport, signal transduction and cell proliferation [1]. Sumoylation involves the covalent attachment of a small ubiquitin like modifier (SUMO) protein to ε-amino group of lysine residues in specific target proteins via a sequential action of an activating enzyme E1 (SUMO E1), a conjugating enzyme E2 and a ligase E3. Among the sumoylation proteins, SUMO E1 is responsible for the activation of SUMO in the first step of the sumoylation cascade [2]. SUMO E1 is linked to many human diseases including cancer and thus making it a potential therapeutic target [3]. However, only a few inhibitors were reported up to now that includes three natural products, semi-synthetic protein inhibitors and one AMP mimic [46]. Here in this research, the combination of structure based virtual screening and in vitro sumoylation assay was used to identify potential small molecule inhibitors of SUMO E1 that could be used in chemical biology and therapeutic studies. Our virtual screening protocol involves the fast docking of a small molecule library to rigid protein followed by redocking of top hits using a method that incorporates both ligand and protein flexibility. Subsequently, the top ranking compounds were prioritized using molecular dynamics simulation based binding free energy calculation. The result of biological assay and subsequent similarity search resulted in the identification of two classes of small molecules that shared biaryl urea scaffold. Both of these chemical classes displayed moderate inhibitory potency against SUMO E1. The most potent compound of each class inhibited the in vitro sumoylation with an IC50 of 11.1 and 13.4 μM. These compounds inhibit sumoylation by blocking the formation of SUMO-E1 thioester intermediate. Our study presents starting points for the development of novel therapeutic agents against various diseases targeting SUMO E1.


  1. Geiss-Friedlander R, Melchior F: Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol. 2007, 8: 947-956. 10.1038/nrm2293.

    Article  CAS  Google Scholar 

  2. Lois LM, Lima CD: Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J. 2005, 24: 439-451. 10.1038/sj.emboj.7600552.

    Article  CAS  Google Scholar 

  3. Kessler JD, Kahle KT, et al: A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis. Science. 2012, 335: 348-353. 10.1126/science.1212728.

    Article  CAS  Google Scholar 

  4. Fukuda I, Ito A, et al: Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem Biol. 2009, 16: 133-140. 10.1016/j.chembiol.2009.01.009.

    Article  CAS  Google Scholar 

  5. Lu X, Olsen SK, et al: Designed semisynthetic protein inhibitors of Ub/Ubl E1 activating enzymes. J Am Chem Soc. 2010, 132: 1748-1749. 10.1021/ja9088549.

    Article  CAS  Google Scholar 

  6. Soucy TA, et al: An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009, 458: 732-736. 10.1038/nature07884.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and permissions

About this article

Cite this article

Kumar, A., Ito, A., Hirohama, M. et al. Identification of SUMO activating enzyme 1 inhibitors utilizing virtual screening approach. J Cheminform 6 (Suppl 1), P37 (2014).

Download citation

  • Published:

  • DOI: