Human papillomavirus (HPV) causes several epithelial cancers, particularly, cervical cancer. Its genome consists of several oncoproteins, among which E7 inactivates a tumor suppressor, retinoblastoma protein (pRb). pRb regulates the cell cycle and apoptosis. HPV-E7 binds to pRb and therefore leads to unregulated cell cycle. In a recent study, a high-throughput screen of ~88000 compounds resulted in seven small molecules which can inhibit the binding of HPV-E7 to pRb. All compounds contain a thiadiazolidinedione ring with a phenyl group bound to it. However, the exact binding mechanism of these compounds to pRb and how they prevent the binding of HPV-E7 to pRb is unknown. We performed molecular dynamics on pRb/inhibitor and pRb/E7 systems to shed light on the binding mechanisms. Our results indicate that the inhibitors very likely bind to the same position of E7. We will also discuss the detailed binding modes and differences in binding energies among several inhibitors.

Computational investigation of the mechanisms for small molecule antagonists of pRb inactivation by HPV-E7

245th National Meeting (2013)

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