The “RAS-RAF-MEK-ERK” pathway is an important signaling pathway in melanoma. BRAFV600E(70–90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (aC-IN/DFG-IN), type II (aC-IN/DFG-OUT), type I1/2(aC-OUT/DFG-IN), and type I/II (aC-OUT/DFG-OUT). First-and second-generation BRAF inhibitors show resistance to BRAFV600Eand are ineffective against malignancies induced by dimer BRAF mutants causing ‘paradoxical’ activation. In the present study, we performed molecular modeling of pyrimidine–sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAFV600Einhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600Einhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600Eprotein than previous inhibitors. Similar to the FDA-approved BRAFV600Einhibitors the developed compounds have [aC-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful againstBRAFV600Eresistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600Eselectiveinhibitors.