Exploration of Anticancer Potential of Novel Pyrrolo[2,3-b]pyridine Derivatives Targeting V600E-BRAF Kinase: Molecular Docking, Pharmacokinetic and DFT Studies

V600E-BRAF mutation has been detected in several malignant tumours. Developing potent V600E-BRAF inhibitors is considered an essential step in curing diverse cancer types. In this work, computational techniques such as the molecular docking simulation, ADMET evaluation, and density functional theory (DFT) calculations were applied to screen and identify the most potential V600E-BRAF inhibitors from a series of 39 previously synthesized novel pyrrolo[2,3-b]pyridine derivatives. Five top-ranked compounds (3, 18, 32, 33, and 35) with remarkable docking scores, compared to Vemurafenib (FDA-approved V600E-BRAF inhibitor), were selected. The formation of H-bonds and hydrophobic interactions with critical residues for V600E-BRAF as Vemurafenib confirmed the high stability of these complexes. Subsequently, the compounds were screened by analyzing their drug-likeness and ADMET properties. The compounds possess safety agents and effective combination therapy as pharmaceutical drugs. The highest occupied molecular (HOMO) orbital, lowest unoccupied molecular orbital (LUMO), and energy gap values were calculated using the DFT. The molecular electrostatic potential (MEP) was analyzed to illustrate the charge density distributions that could be associated with the biological activity. Therefore, compound 35 emerged as a potential hit with enhanced pharmacological properties and could be presented as a promising cancer drug candidate.