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

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

San Miguel de Tucuman

Congreso; "III Latin American Federation of Biophysical Societies (LAFeBS)", "IX IberoAmerican Congress of Biophysics" y "XLV Reunion Anual SAB 2016"; 2016

Latin American Federation of Biophysical Societies y Sociedad Argentina de Biofísica

Around a 50% of patients with melanoma expressing the protein kinase mutant BRAFV600E, induces proliferation through activation of ERK [1]. Vemurafenib is an inhibitor of BRAF that is used clinically to treat patients with metastatic melanoma expressing BRAFV600E. The main objective of this work is to find new compounds with potential inhibitory activity of BRAF. The new compounds were obtained from a virtual screening. We obtained 19 compounds as potential BRAF inhibitors, from which 6 showed significant inhibitory activities against this enzyme. For the bioassays we use as a model, Lu1205 melanoma cells, which express BRAFV600E, and we analyze ERK phosphorylation as a measure of the activity of BRAF. Several compounds decreased the ERK phosphorylation at concentrations of 50 and 10 µM. More interesting, derivatives 6-OH 2carboxanilide obtained by chemical synthesis were the most active compounds presenting activity at a concentration of 1 µM. Preliminary results withthe MTT technique suggest that drugs used to 10 µM decrease cell viability.To better understand these experimental results, we conducted a study of molecular modeling, in which studies docking and molecular dynamicssimulations were used. We also carried out the analysis per residue for the most active compounds of the series and these results were compared withthose obtained for Vemurafenib and dabrafenib. Our molecular modeling study indicates that this new series of inhibitors might interact in the sameactive site which interact these two well- known inhibitors of BRAF [2]. The main interactions that stabilize the various ligand-receptor complexes are:ALA481, LYS483, LEU514, THR529, TRP531, CYS532, PHE583 and ASP594.