6-OH-2- carboxanilide derivatives, a new series of inhibitors of BRAFV600E obtained from virtual screening. Theoretical and experimental study

MORELLATTO RUGGIERI LUCIANA; CAMPOS LUDMILA E.; ENRIZ RICARDO DANIEL; ANDUJAR SEBASTIAN; GARIBOTTO FRANCISCO MATIAS; VETTORAZZI MARCELA; ALVAREZ SERGIO

San Miguel de Tucuman

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

Around a 50% of patients with melanoma expressing the protein kinasemutant BRAFV600E, induces proliferation through activation of ERK.Vemurafenib is an inhibitor of BRAF that is used clinically to treat pa-tients with metastatic melanoma expressing BRAFV600E. The mainobjective of this work is to find new compounds with potential in-hibitory activity of BRAF. The new compoundswereobtainedfrom a vir-tual screening.We obtained 19 compounds as potential BRAF inhibitors, from which6 showed significant inhibitory activities against this enzyme.For the bioassays we use as a model, Lu1205 melanoma cells, whichexpress BRAFV600E, and we analyze ERK phosphorylation as a mea-sure of the activity of BRAF. Several compounds decreased the ERK phosphorylation at concentrations of 50 and 10 μM. More interesting,derivatives 6-OH-2- carboxanilide obtained by chemical synthesis werethe most active compounds presenting activity at a concentration of 1μM. Preliminary results with the MTT technique suggest that drugsused to 10 μM decrease cell viability.To better understand these experimental results, we conducted a studyof molecular modeling, in which studies docking and molecular dynam-ics simulations were used. We also carried out the analysis per residuefor the most active compounds of the series and these results were com-pared with those obtained for Vemurafenib and dabrafenib. Our molec-ular modeling study indicates that this new series of inhibitors mightinteract in the same active site which interact these two well- knowninhibitors of BRAF. The main interactions that stabilize the variousligand-receptor complexes are: ALA481, LYS483, LEU514, THR529,TRP531, LYS532, PHE583, ASP594 and PHE595.