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Background: Drug re-purposing is one of the cost-effective methods to establish novel therapeutics against many diseases. Established natural products are collected from databases and used to potentially screen them against HPV E6 protein, a critical viral protein. Objective: This study aims to design potential small molecule inhibitors against HPV E6 protein using structure-based approaches. Ten natural anti-cancerous compounds (Apigenin, Baicalein, Baicalin, Ponicidin, Oridonin, Lovastatin, Triterpenoid, Narirutin, Rosmarinic Acid, and Xanthone) were selected by review of the literature. Methods: These compounds were screened using Lipinski Rule of Five. Out of ten compounds, seven were found to satisfy Rule of five. Docking of these seven compounds was carried out using AutoDock software and corresponding Molecular Dynamics Simulations were performed by GROMACS Results: Among the seven compounds docked with the E6 target protein, six compounds showed lesser binding energy than the reference compound, Luteolin. The three-dimensional structures of E6 protein and the corresponding ligand complexes were visualised and analysed using PyMOL whereas the two-dimensional images of protein-ligand interactions were obtained by LigPlot+ software to study the specific interactions. ADME analysis using SwissADME software revealed that all the compounds except Rosmarinic acid have good gastrointestinal absorption and solubility characteristics while Xanthone and Lovastatin showed blood brain barrier penetration properties. Considering the binding energy and ADME analysis, Apigenin and Ponicidin are found to be most suitable for de novo designing of potential inhibitors against the HPV16 E6 protein. Conclusion: Further, synthesis and characterization of these potential HPV16 E6 inhibitors will be carried out and their functional evaluation using cell culture-based assays will be undertaken. |
