New flavone-based arylamides as potential V600E-BRAF inhibitors: Molecular docking, DFT, and pharmacokinetic properties

Abstract

Objectives: The V600E-BRAF protein kinase is an attractive and essential therapeutic target in melanoma and other tumors. However, because of its resistance to the known inhibitors and side effects of some identified inhibitors, new potent inhibitors need to be identified.

Methods: In the present work, in silico strategies such as the molecular docking simulation, DFT (Density-Functional-Theory) computations, and pharmacokinetic evaluation were used to determine potential V600E-BRAF inhibitors from a set of 31 synthesized novel flavone-based arylamides.

Results: The docking result demonstrated that four compounds (10, 11, 28, and 31) had acceptable docking scores (MolDock score of -167.523 kcal mol^-1, -158.168 kcal mol^-1, -160.581 kcal mol^-1,-162.302 kcal mol^-1, and a Rerank score of -124.365, -129.365, -135.878 and -117.081, respectively) appeared as most active and potent V600E-BRAF inhibitors that topped vemurafenib (-158.139 and -118.607 kcal mol^-1). The appearance of H-bonds and hydrophobic interactions with essential residues for V600E-BRAF proved the high stability of these complexes. The energy for the frontier molecular orbitals such as HOMO, LUMO, energy gap, and other reactivity parameters was computed using DFT. The frontier molecular-orbital surfaces and electrostatic potentials (EPs) were investigated to demonstrate the charge-density distributions that might be linked to anticancer activity. Similarly, the chosen compounds revealed superior pharmacological properties according to the drug-likeness rules (bioavailability) and pharmacokinetic properties.

Conclusion: The chosen compounds were recognized as potent V600E-BRAF inhibitors with superior pharmacokinetic properties and could be promising cancer drug candidates.

Keywords: ADMET; Arylamide; DFT; Docking; Drug-likeness; V600E-BRAF.

Figure 1

3D and 2D models for the interactions of chosen complexes (10, 11, and 28).

Figure 2

3D and 2D models for the interactions of chosen complexes (3 1 and Vem.).

Figure 3

Optimized-geometric structures of the investigated ligands (10, 11, 28, and 31).

Figure 4

Frontier molecular-orbital surfaces of the investigated ligands (10, 11, 28, and 31).

Figure 5

Electrostatic potential (EP) of the studied ligands (10, 11, 28, and 31).