Investigation of Novel Imidazole Analogues with Terminal Sulphonamides as Potential V600E-BRAF Inhibitors Through Computational Approaches

The V600E-BRAF protein kinase is a promising and essential therapeutic target in melanoma and other types of tumors. However, its resistance to known inhibitors, as well as the side effects of some identified inhibitors, necessitates the search for new and potent inhibitors. In this study, in-silico strategies such as Molecular-docking simulation, DFT (Density-Functional-Theory) computations, and Pharmacokinetic evaluation were used to identify potential V600E-BRAF inhibitors from a set of 38 novel imidazole analogs with terminal sulphonamides. The docking results showed that five compounds (4, 15, 24, 26, and 27), had remarkable docking score (MolDock-score of -186.01, -180.58, -170.89, -177.24 and − 189.24 kcalmol − 1 and Rerank-score of -132.79, -144.43, -136.56, -140.15 and − 136.74 kcalmol − 1 ) and appeared to be the most active and potent V600E-BRAF inhibitors than Vemurafenib (-158.14 kcalmol − 1 and − 118.61 kcalmol − 1 ). The high stability of these complexes was demonstrated by H-bond formation and hydrophobic interactions with essential residues of V600E-BRAF . DFT was used to calculate the energy for the frontier molecular orbitals such as HOMO, LUMO, energy gap, and other reactivity parameters. The charge-density distributions associated with anti-cancer activity were investigated using frontier molecular-orbital surfaces and electrostatic potentials (EPs). Similarly, the chosen compounds demonstrated potentially some interesting pharmacological properties (bioavailability) and pharmacokinetic properties according to drug-likeness rules. As a result, the selected compounds were identified as possible V600E-BRAF hits with eventually superior pharmacokinetic properties, and they could be proposed as promising cancer drug candidates.