Background In previously reported screens of libraries for small molecule compounds that inhibit the apoptotic actions of the viral oncoprotein HPV E6 by blocking interaction with procaspase 8, we reported on two structurally distinct lead molecules, myricetin1 and spinacine2. The purpose of this study was, for each of the ligands, characterize their binding and their respective binding sites on HPV E6. Molecular Modeling Initial exploration to identify the location of the binding of each ligand to the E6 protein was performed using SwissDock3. The E6 model used was molecule C of the crystal structure 4GIZ.pdb4. Both myricetin and spinacine were available in the ZINC database5 for direct use with this online software. Further modeling an optimization will be presented. Myricetin. This flavonol was found to dock to a well-fitting pocket on the surface of the E6 protein. How this might interfere with E6-protein interactions. Spinacine. This amino acid derivative was found to best dock in a more exposed portion of the E6 protein near the coordinated metal of the protein. Isothermal Calorimetry (ITC) Data We intend to present information relating to the ITC data of each ligand with the E6 protein as a means of providing evidence for the model of interation presented from the modeling studies. References (1) Yuan, C.-H.; Filippova, M.; Tungteakkhun, S.S.; Duerksen-Hughes, P.J.; Krstenansky, J.L. Bioorg. Med. Chem. Lett., 2012, 22, 2125. Yuan, C.-H.; Filippova, M.; Krstenansky, J.L.; Duerksen-Hughes, P.J. Cell Death and Disease, 2015, submitted for publication. Grosdidier A.; Zoete V.; Michielin O. Nucleic Acids Res. 2011, 39(Web Server issue), W270. URL: http://www.swissdock.ch/ Zanier, K.; Charbonnier, S.; Sidi, A.O.; McEwen, A.G.; Ferrario, M.G.; Poussin-Courmontagne, P.; Cura, V.; Brimer, N.; Babah, K.O.; Ansari, T.; Muller, I.; Stote, R.H.; Cavarelli, J.; Vande Pol, S.; Trave, G. Science 2013, 339, 694. Irwin, J.J.; Sterling, T.; Mysinger, M.M.; Bolstad, E.S.;Coleman, R,G. J. Chem. Inf. Model. 2012, 52 (7), 1757.

Characterization of small molecule inhibitors of HPV E6

251st National Meeting (2016)

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