Identification of small molecule inhibitors against UBE2C by using docking studies.

Kesavan Sabitha,Thangarajan Rajkumar

doi:10.6026/97320630081047

Abstract

An increased expression of UBE2C (Ubiquitin-conjugating enzyme E2C) has been associated with high tumor grade and cancer progression. It is an essential indicator of the mitotic destruction events. Our microarray study on cervical cancers showed UBE2C to be over expressed in cervical cancer. Subsequent studies from our laboratory, showed that inhibition of UBE2C can enhance radiation and chemosensitivity. Therefore it can be an appropriate target for drug development to identify potential and specific inhibitor of cancer. To identify small molecule inhibitors, a computational approach was used to model UBE2C and further docking studies were carried out. Different ligand subsets such as ChemBank, PDB, KEGG, Drug-likeness NCI, Not annotated NCI of ligand library ligands were downloaded and docked with UBE2C. Schrodinger tools were used for identifying active sites and docking studies of ligands with UBE2C. Based on glide score, the potential ligands were screened and its interaction with UBE2C was identified. We also analyzed the drug like properties such as absorption, distribution, metabolism, excretion and toxicity (ADME/T) of docked compounds. Our results suggest that 2,4-diimino-1-methyl-1,3,5-triazepan-6-one, sulfuric acid compound with 5,6-diamino-2,4-pyrimidinediol (1:1) and 7-alpha-d-ribofuranosyl-2-aminopurine-5'-phosphate may act as best inhibitors and further in vitro studies, may lead to development of novel and best inhibitor of UBE2C.

Highlights

The ubiquitin conjugating enzyme 2C (UBE2C) protein is an anaphase promoting complex and cyclosome (APC/C)-specific ubiquitin-conjugating enzyme. It has a critical role in APC/Cdependent M-phase cell-cycle progression by inactivating the M-phase check point by targeted degradation of short lived proteins [1, 2]. It plays a role in mitotic spindle checkpoint control [3].Cells which are over expressing UBE2C ignore the mitotic spindle checkpoint signals and lose genomic stability accelerating cell proliferation[4,5,6]
The stereochemical properties of UBE2C model was evaluated by Ramachnadran plot after protein preparation script of Schrodinger. 96.5% of the residues were in the favored region, 2.8% were in the allowed region and only 0.7% was in the disfavored region .These results indicate that the phi and psi back-bone dihedral angles in the UBE2C model are accurate [33,34]
It directs polyubiquitination and in addition to its role in cyclin B destruction that is essential for exit from mitosis, UBE2C plays an important role in mitotic spindle checkpoint control

Summary

Introduction

The ubiquitin conjugating enzyme 2C (UBE2C) protein is an anaphase promoting complex and cyclosome (APC/C)-specific ubiquitin-conjugating enzyme. It has a critical role in APC/Cdependent M-phase cell-cycle progression by inactivating the M-phase check point by targeted degradation of short lived proteins [1, 2]. UBE2C has been shown to be preferentially over expressed in cancers compared to 17 other E2 genes [7] In this manuscript we describe computational studies to design specific inhibitors for UBE2C. Computational techniques have become crucial components of many drug discovery programmers, such as hit identification to lead optimization and structure based virtual screening [11,12,13]

Methods

Results

Conclusion