A theoretical and experimental study of two new structural scaffold of BRAF inhibitors

FRANCISCO GARIBOTO; LUDMILA CAMPOS; EMILLIO ANGELINA ; MARCELA VETTORAZZI; M. NATALIA C. ZARYCZ; SERGIO E. ALAVAREZ ; R. DANIEL ENRIZ

Encuentro Virtual

Congreso; Biofísica en tiempos de COVID-19 : Primeras Jornadas Virtuales SAB 2020; 2020

Considering the data from our previous article (1), here we studied two series of derivatives of structural scaffolds as potential BRAF inhibitors: hydroxynaphthalenecarboxamides and substituted piperazinylpropandiols. Our results indicate that structural analogues of substituted piperazinylpropandiols do not show significantly better activities to that previously reported. In contrast, the hydroxynaphthalenecarboxamides derivatives significantly inhibited cell viability and ERK phosphorylation, a measure of BRAF activity, in Lu1205 BRAFV600E melanoma cells. In order to better understand these experimental results, we carried out a molecular modeling study using different combined techniques: docking, MD simulations and quantum theory of atoms in molecules (QTAIM) calculations. Thus, by using this approach we determined that the molecular interactions that stabilize the different molecular complexes are closely related to Vemurafenib, a well-documented BRAF inhibitor. Furthermore, we found that bi-substituted compounds may interact more strongly respect to the mono-substituted analogues by establishing additional interactions with the DFG-loop at the BRAF-active site. We synthesized and tested a new series of bi-substituted hydroxynaphthalenecarboxamides. Remarkably, all these compounds displayed significant inhibitory effects on the bioassays performed. Thus, the structural information reported here is important for the design of new BRAFV600E inhibitors possessing this type of structural scaffold. References: 1) L.E. Campos, F.M. Garibotto, E. Angelina, J. Kos, T. Toma?ič, N. Zidar, D. Kikelj, T. Gonec, P. Marvanova, P. Mokry, J. Jampilek, S.E. Álvarez and R.D. Enriz; Bioorg. Chem. 2019, 91, 103125