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Dear editor  We have read with great interest the paper by Tang and Chen1 published in the most recent issue of the International Journal of Nanomedicine, in which the authors describe the protocol by which scientists constructed the ideal BRAF (V600E)-modeled structure through homology modeling and introduced the method of structure-based docking or virtual screening from a large compound database. They concluded that BRAF (V600E) has a quite prominent structural or conformational variation when compared to the wild-type BRAF protein by matrix of root mean square fluctuation and principal component analysis. On the basis of structure-based virtual screening, ligand-based quantitative structure activity relationship models, and molecular dynamics simulation, we recommend aknadicine and 16beta-hydroxy-19s-vindolinine N-oxide as potent compounds for developing novel inhibitors in the future.  The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene is mutated in 40%–60% of melanomas, the most common being the V600E mutation, which leads to activation of the mitogen activated protein kinase (MAPK) pathway.2 BRAF is a member of the RAF family of serine/threonine protein kinases. This family consists of three kinases, ie, ARAF, CRAF (RAF-1), and BRAF, of which the latter has the highest basal kinase. BRAF functions to regulate the MAPK/ERK pathway, which is conserved in all eukaryotes. The RAS/RAF/MEK/ERK pathway acts as a signal transducer between the extracellular environment and the nucleus. Extracellular signals such as hormones, cytokines, and various growth factors interact with their receptors to activate the small G-proteins of the RAS family. BRAF-mutated tumors have a poor response to traditional chemotherapy and a poor prognosis in melanoma, thyroid, and colon cancers.3–5 Targeted therapies are of great interest for these types of cancer, and elucidation of the structure and functions of BRAF kinase is the subject of much ongoing research. The approach of targeting oncogenic kinases has been successful in the treatment of cancers with activating mutations in the kinase gene that drives their progression. It is likely that our evolving understanding of BRAF genetics and signaling will allow further personalization of cancer therapy with the goal of improving clinical responses.  We are confident that the results reported Tang and Chen1 have brought progress to the field, but targeting a malignant cell with a monotherapy protocol is expected to fail and thus lead to clinical relapse of the disease. Thus, combination therapy is likely to be the most effective management plan for the treatment of BRAF-mutated tumors. Many BRAF-specific inhibitors display a cytostatic response inducing senescence and are susceptible to acquired resistance. Therefore, combination with traditional chemotherapeutic agents seems to be more effective than either treatment alone.

Small molecules against B-RAF (BRAF) Val600Glu (V600E) single mutation