IMASL   20939
INSTITUTO DE MATEMATICA APLICADA DE SAN LUIS "PROF. EZIO MARCHI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
A theoretical and experimental study of two new structural scaffold of BRAF inhibitors
Autor/es:
CAMPOS, LUDMILA; ZARYCZ, M. NATALIA C.; ENRIZ, DANIEL; GARIBOTTO, FRANCISCO; VETTORAZZI, MARCELA; ALVAREZ, SERGIO; ANGELINA, EMILIO; TOSSO, RODRIGO
Reunión:
Congreso; Primeras jornadas virtuales de la Sociedad Argentina de Biofísica; 2020
Resumen:
Considering the data from our previous article (1), here we studied two series ofderivatives of structural scaffolds as potential BRAF inhibitors:hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols.Our results indicate that structural analogues of substituted piperazinylpropandiols donot show significantly better activities to that previously reported. In contrast, thehydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability andERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells.In order to better understand these experimental results, we carried out a molecularmodeling study using different combined techniques: docking, MD simulations andquantum theory of atoms in molecules (QTAIM) calculations. Thus, by using thisapproach we determined that the molecular interactions that stabilize the differentmolecular complexes are closely related to Vemurafenib, a well-documented BRAFinhibitor. Furthermore, we found that bi-substituted compounds may interact morestrongly respect to the mono-substituted analogues by establishing additionalinteractions with the DFG-loop at the BRAF-active site. We synthesized and tested a newseries of bi-substituted hydroxynaphthalenecarboxamides. Remarkably, all thesecompounds displayed significant inhibitory effects on the bioassays performed. Thus, thestructural information reported here is important for the design of new BRAFV600Einhibitors possessing this type of structural scaffold.