Prediction and Validation of Novel BRAF Inhibitor as a Potential Drug Candidate for the Treatment of Colorectal...

Colorectal cancer (CRC), the world's third leading cause of death, can be caused by a variety of reasons, one of which is a valine-to-glutamate mutation at position 600 in the BRAF gene. Nonetheless, the prognosis of patients with BRAF mutations remains poor, necessitating additional research in this field.

This work aims to recognize and validate innovative and effective BRAF inhibitor.

A merged-featured ligand-based pharmacophore model was validated and screened against various external databases. The pharmacokinetic and toxicological characteristics of the 102 hits were analyzed, and the appropriate ligands were docked against BRAF protein. The top four protein-ligand complexes with the lowest binding energies were chosen, and their Molecular Dynamic (MD) simulation studies were accomplished.

The finest complex selected has a Root Mean Square Deviation (RMSD) value of 2.229A⁰ and a Radius of Gyration (RoG) value of 25.770A⁰. The LC₅₀ of the best ligand was experimentally calculated to be 102.83 μg/ml. The ligand was found to destroy CRC cells, but it did not affect normal non-cancerous cells much.

This work thus proposes 3-(6,7-dimethoxy-3,4-dihydroisoquinoline-2-carbonyl)-N- (2-methoxyphenyl)benzenesulphonamide as a potential BRAF V600E inhibitor for the CRC treatment.