Searching by molecular modeling of new inhibitors of Sphingosine Kinase 1

M. VETTORAZZI; L.GUTIERREZ; S.ROJAS; G. LEZAMA; ENRIZ R D

Samtiago del Estero

Congreso; SAB; 2015

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 resistance. The crystal structure of SphK1 has been recently reported, providing a new direction for the design of new inhibitors of SphK1, which may give more effective and specific inhibitors in the near future. The natural substrate and three synthetic compounds have been recently co-crystallized (PDB code: 3VZB, 3VZD, 4L02, 4V24). 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 molecular dynamics simulations of different molecular systems. Thus, we performed a virtual screening from a library of compounds available, followed by a molecular dynamics simulations and calculation of the binding energies for each complex. Then, we compared this energies with the energies of the crystallized complexes obtains and their respective IC50 value to estimate the inhibitory capacity of these new compounds. Our simulations indicated that compounds INH185 are the most promising candidates to produce the inhibitory effect in this enzyme. Such a compounds displayed G values in the order of -87.3 Kcal/mol. Another group of compounds showing very interesting values of G are INH153 derivatives. A third series that showed energy values in the order of -79.8 Kcal/mol are those structurally related with INH178. On the basis of these results we are performing now the biological assays in order to confirm these theoretical results.