Computational design and evaluation of indolo‐phenazine analogues as anti‐breast cancer agents targeting casein kinase 2α and topoisomerase II

Abstract This study investigates the molecular docking, drug‐likeness, pharmacokinetic properties, and molecular dynamics (MD) simulation of 15 indolo‐phenazine analogues, focusing on their potential as inhibitors for topoisomerase II (5GWK) and casein kinase 2α (3OWJ). Using PyRx software (AutoDock Vina), we docked the ligands and identified IP4 as the most stable compound, forming strong hydrogen bonds with the receptor proteins. The analogues exhibited superior docking scores compared to the standard compound ellipticine, indicating enhanced binding affinity. Drug‐likeness analysis based on Lipinski's Rule of Five demonstrated that all compounds, except IP8, comply with the criteria, and their moderate solubility and synthetic accessibility suggest feasibility for drug development. Pharmacokinetic analysis revealed high gastrointestinal absorption and bioavailability for the analogues, with some compounds exhibiting no blood–brain barrier penetration, implying minimal central nervous system side effects. Target prediction suggested that the compounds, particularly IP4 and IP9, exhibit stronger kinase inhibition compared to ellipticine. MD simulations further supported the binding stability, with IP2 showing more favorable stability and fewer structural fluctuations compared to ellipticine. MM‐GBSA calculations revealed that ellipticine forms a more stable binding complex with 3OWJ, primarily due to favorable hydrophobic and van der Waals interactions. Overall, these findings highlight the promising drug‐like properties of indolo‐phenazine derivatives, especially IP4 and IP9, for potential anticancer applications through kinase inhibition. These findings provide insights into their molecular interactions and pharmacological properties, suggesting these analogues as lead candidates providing a foundation for synthesizing and evaluating the pharmacological activity of Indolo‐phenazine analogues as kinase‐inhibiting, anti‐breast cancer agents.