Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31401373
DOI
10.1016/j.bioorg.2019.103125
PII: S0045-2068(19)30532-2
Knihovny.cz E-resources
- Keywords
- BRAF inhibitors, Bioassays, Molecular modeling, Synthesis, Virtual screening,
- MeSH
- Protein Kinase Inhibitors chemical synthesis metabolism pharmacology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Antineoplastic Agents chemical synthesis metabolism pharmacology MeSH
- Proto-Oncogene Proteins B-raf antagonists & inhibitors metabolism MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- Protein Binding MeSH
- Vemurafenib pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- BRAF protein, human MeSH Browser
- Protein Kinase Inhibitors MeSH
- Antineoplastic Agents MeSH
- Proto-Oncogene Proteins B-raf MeSH
- Vemurafenib MeSH
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.
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