The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic options. The main objective of this work was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Our study was carried out in different stages; in the first step we performed a virtual screening that allowed us to identify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of the novel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understand interactions at the molecular level that stabilize the formation of the different molecular complexes. Our theoretical and experimental study allowed the identification of four new structural scaffolds, which could be used as starting structures for the design and development of new inhibitors of BRAF. Our experimental data indicate that the most active compounds reduced significantly ERK½ phosphorylation, a measure of BRAF inhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substituted hydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanols and substituted piperazinylpropandiols as initial structures for the development of new inhibitors for BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of the different molecules must be changed in order to obtain an increase in the binding affinity of these new ligands.

Department of Analytical Chemistry Faculty of Natural Sciences Comenius University Ilkovicova 6 84215 Bratislava Slovakia

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Palackeho 1 61242 Brno Czech Republic

Division of Biologically Active Complexes and Molecular Magnets Regional Centre of Advanced Technologies and Materials Faculty of Science Palacky University Olomouc Slechtitelu 27 78371 Olomouc Czech Republic

Facultad de Química Bioquímica y Farmacia Universidad Nacional de San Luis Ejército de los Andes 950 5700 San Luis Argentina

Instituto Multidisciplinario de Investigaciones Biológicas Ejército de los Andes 950 5700 San Luis Argentina

Laboratorio de Estructura Molecular y Propiedades Área de Química Física Departamento de Química Facultad de Ciencias Exactas y Naturales y Agrimensura Universidad Nacional del Nordeste Avda Libertad 5460 3400 Corrientes Argentina

University of Ljubljana Faculty of Pharmacy Aškerčeva 7 1000 Ljubljana Slovenia

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