Polymorphisms at site 469 of B-RAF protein associated with skin melanoma may be correlated with dabrafenib resistance: An in silico study

Abstract

Melanoma is a type of skin cancer. Numerous genes and their proteins are strongly associated with melanoma susceptibility. This study aims to use an in silico method to identify genetic variants in the melanoma susceptibility gene. The COSMIC database was queried for genes and cross-referenced with three environment–gene interaction databases (EGP, SeattleSNPs and CTD) to identify shared genes. The majority of approved skin melanoma drugs were found to act on the protein serine/threonine-protein kinase (B-RAF) encoded by the BRAF gene, which was also present in all three referenced databases. Comprehensive computational analysis was performed to predict deleterious genetic variants associated with skin melanoma, and the nsSNPs G469V and G469E were prioritized based on their predicted deleterious effects. Molecular dynamic simulation analysis of the B-RAF protein mutants G469V and G469E reveals that variations in the amino acid conformation at the drug binding site result in inconsistency in drug interaction. Additionally, this analysis showed that the G469V and G469E mutants have lower binding energy for dabrafenib than the wild type. The population with the highest frequency of each deleterious and pathogenic variant has been determined. The study's findings would support the development of more effective treatment strategies for skin melanoma.

Communicated by Ramaswamy H. Sarma

Keywords:

• Skin melanoma
• B-RAF mutants
• G469V
• G469E
• dabrafenib

Disclosure statement

No potential conflict of interest was reported by the authors.