Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Interaction of Porphyrin-Anthraquinone Hybrids with HSP90: In Silico Study
Cationic porphyrin-anthraquinone hybrids bearing meso-substituents, either pyridine, imidazole, or pyrazole rings have been investigated for their interaction with Hsp90. Nine porphyrin hybrids were docked to Hsp90 i.e. tris-H2ImP-AQ, tris-H2PyP-AQ, tris-H2PzP-AQ, bis-H2ImP-AQ, bis-H2PyP-AQ, bis-H2PzP-AQ, mono-H2ImP-AQ, mono-H2PyP-AQ, mono-H2PzP-AQ, as well as native ligand (Geldanamycin, GD). Monitoring of conformational changes of ligand-Hsp90 complexes during 6 ns was performed by Amber12 molecular dynamics package, while binding energy calculation of each complex was carried out using MM-PBSA method (Kollman et al., 2000).
Interaction of porphyrin hybrids with Hsp90 occurred through the binding site of Hsp90, in which each ligand except for bis-H2ImP-AQ was able to form hydrogen bond with Phe138 residue. The hydrogen bond was also established between porphyrin and Asp54 as observed in all ligands except for bis-H2ImP-AQ and tris-H2ImP-AQ. The additional pi-cationic interactions between porphyrin and Lys58, and between benzene ring and Lys112 were observed, which was absent in the interaction of GD. The six-ns molecular dynamics simulation confirmed the stability of the ligand-Hsp90 complexes, while residue fluctuation analysis indicated that each complex has similar RMSF distribution. Prediction of binding free energy showed that favorable energy contribution was originated from electrostatic, van der Waals, and nonpolar desolvation energies. The binding energy of each ligand was more negative compared to that of GD, indicating the potential of designed ligands to be developed as new Hsp inhibitor.
Kollman, P.A., Massova, I., Reyes, C., Kuhn, B., Huo, S., Chong, L., Lee, M., Lee, T., Duan, Y., Wang, W., Donini, O., Cieplak, P., Srinivasan, J., Case, D.A., & Cheatham, T.E. (2000). Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Account of Chemical Research, 33, 889â-897.
School of Pharmacy