In Silico Studies of Novel Vemurafenib Derivatives as BRAF Kinase Inhibitors

BRAF inhibitors have improved the treatment of advanced or metastatic melanoma in patients that harbor a BRAF(T1799A) mutation. Because of new insights into the role of aberrant glycosylation in drug resistance, we designed and studied three novel vemurafenib derivatives possessing pentose-associated aliphatic ligands—methyl-, ethyl-, and isopropyl-ketopentose moieties—as potent BRAF(V600E) kinase inhibitors. The geometries of these derivatives were optimized using the density functional theory method. Molecular dynamic simulations were performed to find interactions between the ligands and BRAF(V600E) kinase. Virtual screening was performed to assess the fate of derivatives and their systemic toxicity, genotoxicity, and carcinogenicity. The computational mapping of the studied ligand–BRAF(V600E) complexes indicated that the central pyrrole and pyridine rings of derivatives were located within the hydrophobic ATP-binding site of the BRAF(V600E) protein kinase, while the pentose ring and alkyl chains were mainly included in hydrogen bonding interactions. The isopropyl-ketopentose derivative was found to bind the BRAF(V600E) oncoprotein with more favorable energy interaction than vemurafenib. ADME-TOX in silico studies showed that the derivatives possessed some desirable pharmacokinetic and toxicologic properties. The present results open a new avenue to study the carbohydrate derivatives of vemurafenib as potent BRAF(V600E) kinase inhibitors to treat melanoma.