SEARCH OF NEW STRUCTURAL SCAFFOLDS FOR SPHINGOSINE KINASE 1 INHIBITORS

VETTORAZZI, MARCELA; ROJAS, SEBASTIÁN; GUTIÉRREZ, LUCAS; ANDUJAR, SEBASTIÁN; ÁLVAREZ, SERGIO; ENRIZ, DANIEL

San Miguel de Tucuman

Congreso; III Latin American Federation of Biophysical Societies (LAFeBS). IX IberoAmerican Congress of Biophysics. XLV Reunión Anual de la Sociedad Argentina de Biofísica (SAB); 2016

Universidad Nacional de Tucuman

Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactivesphingolipid metabolite, sphingosine-1-phosphate, is a promising newmolecular target for therapeutic intervention in cancer and inflammatorydiseases[1,2]. In view of its importance, the main objective of this workwas to find new and more potent inhibitors for this enzyme possessingdifferent structural scaffolds than those of the known inhibitors. Ourtheoretical and experimental study has allowed us to find two new struc-tural scaffolds (three new compounds), which could be used as startingstructures for the design and then the development of new inhibitors ofSphK1. Our study was carried out in different steps: virtual screening,synthesis, bioassays and molecular modeling. From our results, we pro-pose new dihydrobenzo[b]pyrimido[5,4-f]azepines, and two pyridinyl-piperazinyl-ethyl-phenyl-O-alkyl-carbamate derivatives as initial struc-tures for the development of new inhibitors for SphK1. In addition,our molecular modeling study using QTAIM calculations, allowed us todescribe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analyses indicate that the cationic head of the different compounds must be refined in order to obtain an increase in the binding affinity of these ligands.