Docking-based strategy to design novel flavone-based arylamides as potent V600E-BRAF inhibitors with prediction of their drug-likeness and ADMET properties

Abstract

V600E-BRAF protein target has much potential for scientific research as therapeutic target due to its involvement in human melanoma cancer. In the current research, molecular docking investigation was conducted on some flavone-based arylamides as anticancer drug candidates via V600E-BRAF inhibition with the help of docking software Molegro Virtual Docker. Based on the predicted results, existing structures were modified and screened for pharmacokinetics ADMET properties. The docking result demonstrates that compound 28 best inhibits V600E-BRAF when compared with other compounds within the dataset. This compound was used as a template in designing novel anticancer compounds by attaching some favorable substituents. The docking results of the designed compounds revealed a good MolDock score (< − 90), which showed that all the compounds can efficiently bind with the active sites of the target, out of which two analogous (N1 and N3) were considered optimal that outperformed vemurafenib, the FDA-approved V600E-BRAF inhibitor. Furthermore, these compounds passed the drug-likeness criteria (Lipinski’s rule) successfully and were found to be orally bioavailable. Also, the designed compounds were found to have good pharmacokinetics absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Thus, this study identified compounds (N1 and N3) as the best hits against V600E-BRAF kinase with enhanced pharmacological properties and recommends their synthesis, in vivo and ex vivo evaluation to validate our hypothesis.