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

VETTORAZZI MARCELA; ANDUJAR SEBASTIAN; GUTIÉRREZ LUCAS J.; SUVIRE FERNANDO; ENRIZ, RICARDO D.

Congreso; XLIII Reunión Anual SAB 2014; 2014

A QM/MM study of the molecular interactions of different ligands and Sphingosine Kinase1 (SphK1) Vettorazzi, M.ab; Andujar, S.ab ; Gutierrez, L c; Suvire, F.ab ; Alvarez, S.ab ; Enriz, D. ab a Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Chacabuco 915, 5700 San Luis, Argentina. b IMIBIO-SL (CONICET), Chacabuco 915, 5700 San Luis, Argentina. c Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste. Av. Libertad 5470, 3400 Corrientes, Argentina 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 two synthetic compounds have been recently co-crystallized (PDB code: 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.