Targeting the ubiquitin-conjugating enzyme E2D4 for cancer drug discovery–a structure-based approach
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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.
KeywordsActive site ADME Cancer Homology modelling Protein-protein docking Virtual screening
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
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.
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