A QM/MM study of the molecular interactions of different ligands andSphingosine Kinase1 (SphK1),

M.VETTORAZZI; S. ANDUJAR; L.GUTIERREZ; ENRIZ R D

Sierra de la Ventana

Congreso; SAB; 2014

SAB

The potential of the sphingolipid metabolic pathway for the development of therapeutic targets for cancer has been recognized for years. Thus, inhibition of SphK1 is considered a novel approach for the treatment of cancers including metastatic cancer and/or multi drug resistence. So far, the development of SKIs has been hampered by the lack of a crystal structure of SphK1, and therefore, rational drug design was impractical. A recent report describing the crystal structure of SphK1 is expected to provide a new direction to SKI design, which may lead to more effective and specific inhibitors in the near future. The natural substrate and two synthetic compounds have been recently co-crystallized (PDB code: 3BZB, 3BZD and 4L02). These inhibitors interact at the hydrophobic region in the same way but display very different molecular interactions in the polar region of the binding site. In this study, we performed first molecular dynamics simulations of the different molecular systems and in a second step we applied a hybrid Quantum mechanical-molecular Mechanical (QM/MM) method followed by a Quantum Theory of Atoms in Molecules (QTAIM) analysis to investigate the ligand-receptor interactions of the different complexes. The affinities of the ligands were evaluated in terms of the electron density (p (r) at the intermolecular bond critical points.