ZINC1797251, a novel natural product small molecule targets viral oncoprotein E6 in human papillomavirus-16 positive cervical cancer cells

Cervical cancer burden due to recurrent human papillomavirus (HPV) infections necessitates the urgent need to impede viral proliferation targeting the oncogene E6 of the high-risk serotype HPV16. This study aims to identify a small molecule from a natural product library that could prevent a tumorigenic complex of E6 with p53 in HPV16-positive cervical cancer cells. <i>In silico</i> methods such as high-throughput virtual screening (HTVS) of natural product like library ZINC database followed by atomistic molecular dynamics (MD) simulations were performed to identify lead natural compound. This was validated with <i>in vitro</i> analysis using HPV16 positive SiHa cells and CaSki cells by MTT and flow cytometry assays. Virtual screening identified top 10 compounds with high affinity for HPV16 E6. The docking scores, Protein-Ligand Interaction Profiler analysis, MD simulation and molecular mechanics Poisson Boltzmann surface area-based binding energy estimation narrowed down the search to ZINC1797251, a molecule with stable binding, low energy scores and consistent H-bonds, establishing that it could prevent interaction of p53 and E6. ZINC1797251 inhibited the proliferation of SiHa and CaSki cells with a G_I50 values of 615.40 and 417.30 nM, respectively. The compound reduced HPV16 E6, while increased p53 positive populations in SiHa and CaSki cells. Treatment with ZINC1797251 induced the G₁ cell phase arrest and promoted early and late phase apoptosis in these cells. The restoration of tumor inhibitory activity of p53 in HPV-infected cervical cancer cells to promote apoptosis could be achieved using the ZINC molecule-ZINC1797251. However, further studies are deemed essential for further developments.