Abstract
High risk human papillomaviruses are highly associated with the cervical carcinoma and the other genital tumors. Development of cervical cancer passes through the multistep process initiated from benign cyst to increasingly severe premalignant dysplastic lesions in an epithelium. Replication of this virus occurs in the fatal differentiating epithelium and involves in the activation of cellular DNA replication proteins. The oncoprotein E7 of human papillomavirus expressed in the lower epithelial layers constrains the cells into S-phase constructing an environment favorable for genome replication and cell proliferation. To date, no suitable drug molecules exist to treat HPV infection whereas anticipation of novel anti-HPV chemotherapies with distinctive mode of actions and identification of potential drugs are crucial to a greater extent. Hence, our present study focused on identification of compounds analogue to EGCG, a green tea molecule which is considered to be safe to use for mammalian systems towards treatment of cancer. A three dimensional similarity search on the small molecule library from natural product database using EGCG identified 11 potential small molecules based on their structural similarity. The docking strategies were implemented with acquired small molecules and identification of the key interactions between protein and compounds were carried out through binding free energy calculations. The conformational changes between the apoprotein and complexes were analyzed through simulation performed thrice demonstrating the dynamical and structural effects of the protein induced by the compounds signifying the domination. The analysis of the conformational stability provoked us to describe the features of the best identified small molecules through electronic structure calculations. Overall, our study provides the basis for structural insights of the identified potential identified small molecules and EGCG. Hence, the identified analogue of EGCG can be potent inhibitors against the HPV 16 E7 oncoprotein.
Highlights
Cervical cancer is represented as the second most common cancer of women worldwide and is the most common sexually transmitted viral infection[1,2]
The infection caused by human papillomavirus is the common sexually transmitted infection occuring mostly in women and estimated to be around 75–80% in sexually active women
Human papillomavirus infection in human develops a critical role in the common dermatologic, sexually transmitted diseases and some of the frequently occurring cancers worldwide
Summary
Cervical cancer is represented as the second most common cancer of women worldwide and is the most common sexually transmitted viral infection[1,2]. The E7 protein binds to pRb and degrades the suppressor function for uncontrolled activation of E2F transcription factor that kindles the expression of genes involving in the S phase of the cell cycle[23]. It interacts with the other cellular targets namely p16INK4a, Ki-67 and certain specific inhibitors of cyclin-dependent kinases like p21 and p27. CD3 constitutes the region containing CXXC motifs within the residues 38–98 which is responsible for the zinc binding and this motif is involved in the dimerization of the protein[31,36] This domain involves in the interaction with various cellular proteins namely p21 and p27 CDK inhibitors and interacts with the Mi2β component of the histone deacetylase complex and TBP36. It is noticeably implicit that these domains are essential for the abrogation of epithelial cell quiescence and they contribute to the cellular transformation[31,37,38]
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