Exploration of Anticancer Potential of Novel Pyrrolo[۲,۳-b]pyridine Derivatives Targeting V۶۰۰E-BRAF Kinase: Molecular Docking, Pharmacokinetic and DFT Studies

V۶۰۰E-BRAF mutation has been detected in several malignant tumours. Developing potent V۶۰۰E-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 V۶۰۰E-BRAF  inhibitors from a series of ۳۹ previously synthesized novel pyrrolo[۲,۳-b]pyridine derivatives. Five top-ranked compounds (۳, ۱۸, ۳۲, ۳۳, and ۳۵) with remarkable docking scores, compared to Vemurafenib (FDA-approved V۶۰۰E-BRAF inhibitor), were selected. The formation of H-bonds and hydrophobic interactions with critical residues for V۶۰۰E-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 ۳۵ emerged as a potential hit with enhanced pharmacological properties and could be presented as a promising cancer drug candidate.