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Journal of Chemical Biology

, Volume 10, Issue 2, pp 51–67 | Cite as

Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach

  • Vishwanath Ramatenki
  • Ramakrishna Dumpati
  • Rajender Vadija
  • Santhiprada Vellanki
  • Sarita Rajender Potlapally
  • Rohini Rondla
  • Uma Vuruputuri
Original Article

Abstract

Cancer progression is a global burden. The incidence and mortality now reach 30 million deaths per year. Several pathways of cancer are under investigation for the discovery of effective therapeutics. The present study highlights the structural details of the ubiquitin protein ‘Ubiquitin-conjugating enzyme E2D4’ (UBE2D4) for the novel lead structure identification in cancer drug discovery process. The evaluation of 3D structure of UBE2D4 was carried out using homology modelling techniques. The optimized structure was validated by standard computational protocols. The active site region of the UBE2D4 was identified using computational tools like CASTp, Q-site Finder and SiteMap. The hydrophobic pocket which is responsible for binding with its natural receptor ubiquitin ligase CHIP (C-terminal of Hsp 70 interacting protein) was identified through protein-protein docking study. Corroborating the results obtained from active site prediction tools and protein-protein docking study, the domain of UBE2D4 which is responsible for cancer cell progression is sorted out for further docking study. Virtual screening with large structural database like CB_Div Set and Asinex BioDesign small molecular structural database was carried out. The obtained new ligand molecules that have shown affinity towards UBE2D4 were considered for ADME prediction studies. The identified new ligand molecules with acceptable parameters of docking, ADME are considered as potent UBE2D4 enzyme inhibitors for cancer therapy.

Keywords

Active site ADME Cancer Homology modelling Protein-protein docking Virtual screening 

Notes

Acknowledgements

The author VR acknowledges the Council of Scientific and Industrial Research, India, for the financial support (File No: 09/132(0821)/2012-EMR-I). The authors VR, RKD, RV, SPV and RR acknowledge the Principal and Head, Department of Chemistry, University College of Science, Osmania University, Hyderabad, for providing facilities to carry out this work.

Compliance with ethical standards

Ethical standards

The authors state that no human studies and no animal studies were carried out for this article.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12154_2016_164_Fig13_ESM.gif (7.5 mb)
Supplementary fig S1

Alignment of the UBE2D4 sequence with the other E2 sequences. The alignment file was generated using CLUSTALW server tool. The UBC domain of UBE2D4 is conserved in all the E2s. The UBE2D4 conserved domain sequence starts from LYS 4 and ends with THR 142 amino acid residue. (GIF 7718 kb)

12154_2016_164_MOESM1_ESM.tif (12.8 mb)
High Resolution (TIFF 13149 kb)
12154_2016_164_MOESM2_ESM.docx (17 kb)
Supplementary Table S1 (DOCX 17 kb)
12154_2016_164_MOESM3_ESM.docx (100 kb)
Supplementary Table S2 (DOCX 100 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Vishwanath Ramatenki
    • 1
  • Ramakrishna Dumpati
    • 1
  • Rajender Vadija
    • 1
  • Santhiprada Vellanki
    • 1
  • Sarita Rajender Potlapally
    • 2
  • Rohini Rondla
    • 1
  • Uma Vuruputuri
    • 1
  1. 1.Department of Chemistry, University College of ScienceOsmania UniversityHyderabadIndia
  2. 2.Department of Chemistry, Nizam CollegeOsmania UniversityBasheerbagh, HyderabadIndia

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