Searching by molecular modeling of new inhibitors of Sphingosine Kinase 1

VETTORAZZI, MARCELA; GUTIERREZ, LUCAS; ANDUJAR, SEBASTIAN

Congreso; Sociedad Argentina de Biofísica; 2015

p { margin-bottom: 0.21cm; direction: ltr; color: rgb(0, 0, 0); }p.western { font-family: "Times New Roman",serif; font-size: 12pt; }p.cjk { font-family: "Droid Sans Fallback","MS Mincho"; font-size: 12pt; }p.ctl { font-family: "Lohit Hindi","MS Mincho"; font-size: 12pt; }Thepotential of the sphingolipid metabolic pathway for the developmentof therapeutic targets for cancer has been recognized for years.Thus, inhibition of SphK1 is considered a novel approach for thetreatment of cancers including metastatic cancer and/or multi drugresistance. The crystal structure of SphK1 has been recentlyreported, providing a new direction for the design of new inhibitorsof SphK1, which may give more effective and specific inhibitors inthe near future. The natural substrate and three synthetic compoundshave been recently co-crystallized (PDB code: 3VZB, 3VZD, 4L02,4V24). These inhibitors interact at the hydrophobic region in thesame way but display very different molecular interactions in thepolar region of the binding site. In this study, we performedmolecular dynamics simulations of different molecular systems. Thus,we performed a virtual screening from a library of compoundsavailable, followed by a molecular dynamics simulations andcalculation of the binding energies for each complex. Then, wecompared this energies with the energies of the crystallizedcomplexes obtains and their respective IC50value to estimate the inhibitory capacity of these new compounds. Oursimulations indicated that compounds INH185 are the most promisingcandidates to produce the inhibitory effect in this enzyme. Such acompounds displayed Gvalues in the order of -87.3 Kcal/mol. Another group of compoundsshowing very interesting values of Gare INH153 derivatives. A third series that showed energy values inthe order of -79.8 Kcal/mol are those structurally related withINH178. On the basis of these results we are performing now thebiological assays in order to confirm these theoretical results.