A QM/MM study of the molecular interactions of different ligands and Sphingosine Kinase1 (SphK1)

VETTORAZZI M; ANDUJAR S; GUTIERREZ L; SUVIRE F; ALVAREZ SE; ENRIZ D

Congreso; XLIII Reunion Anual de la Sociedad Argentina de Biofisica; 2014

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 resistance. 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 twosynthetic compounds have been recently co-crystallized (PDBcode: 3VZB, 3VZD 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 (ρ (r)) at the intermolecular bond critical points.