Structural dynamic studies on identification of EGCG analogues for the inhibition of Human Papillomavirus E7

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.

Figure 1

(a) Structure of EGCG and (b) superimposition of all the retrieved 11 compounds analogue to EGCG.

Figure 2

2 Dimensional Interaction diagram of the best identified small molecule compounds obtained during the Glide XP docking.

Figure 3

Binding pocket amino acid residue interaction patterns of bound best identified small molecule compounds during the Glide XP docking. Hydrogen bonds are depicted by a yellow dotted line.

Figure 4

2 Dimensional Interaction diagram of the best identified small molecule compounds obtained during the Induced Fit docking.

Figure 5

Binding pocket amino acid residue interactions patterns of bound best identified small molecule compounds during the Induced Fit docking. Hydrogen bonds are depicted by a yellow dotted line.

Figure 6

Electronic structure calculation studies of the best identified small molecule compounds and the reference compound EGCG.

Figure 7

(a) RMSD plots of the best identified small molecule compounds and EGCG with the HPV E7 oncoprotein (b) RMSF plots of the best identified small molecule compounds and EGCG with the HPV E7 oncoprotein (c) Mean RMSD of the best identified small molecule compounds and EGCG with the HPV E7 oncoprotein.

Figure 8

(a) RMSD plots of the best identified small molecule compound ZINC49069570 with the HPV E7 oncoprotein for three sets of simulation (b) Average Mean of the RMSD plots of the best Identified ZINC49069570 with the HPV E7 oncoprotein for three sets of simulation. (c) RMSF plots of the best identified small molecule compound ZINC49069570 with the HPV E7 oncoprotein for three sets of simulation (b) Average Mean of the RMSF plots of the best Identified ZINC49069570 with the HPV E7 oncoprotein for three sets of simulation.

Figure 9

(A) Radius of Gyration plots of the best identified small molecule compounds and EGCG with the HPV E7 oncoprotein (B) Hydrogen Bond analysis of the best identified small molecule compounds and EGCG with the HPV E7 oncoprotein.

Figure 10

Graph showing the distribution of the various interaction energies like binding free energy, van der Waals energy, polar solvation, non-polar solvation energy and Electrostatic energy of the identified ligands and reference molecule.

Figure 11

Principle component analysis of the Modelled HPV E7 oncoprotein, HPV ZINC49069570 complex and HPV EGCG complex represented in Black, Orange and Cyan respectively.

Figure 12

Conformational evolution of secondary structure elements of HPV E7 modelled protein.

Figure 13

Conformational evolution of secondary structure elements of HPV E7 oncoprotein in complex with the Compound ZINC49069570.

Figure 14

Conformational evolution of secondary structure elements of HPV E7 oncoprotein in complex with the Compound EGCG.