This work systematically investigates the interaction of Busulfan (BN), an anticancer drug with established anticancer activity, with DNA/RNA nucleobases employing advanced computational approaches such as density functional theory (DFT), time-dependent density functional theory (TD-DFT), and molecular docking. BN-drug complexes with adenine, guanine, cytosine, thymine, and uracil nucleobases are optimized at the ωB97XD/6- 31++G (d, p) level of theory to get the accurate optimum force and displacement values as 0.00045 Hartree and 0.0018 Bohr, respectively, with the expected energy shift of 1.79 × 10 08 Ha. Various molecular parameters, including adsorption energy (Eads), enthalpy (ΔH), Gibbs free energy (ΔG), quantum descriptors, atom in molecule (AIM), reduced density gradient (RDG), and localized orbitals locator (LOL), are calculated in gas and water media to analyze the BN-drug@nucleobases complexes in detail. The calculated Eads and ΔH values in gas and water media underscore a notably stronger affinity between BN-drug and cytosine/guanine nucleobases than adenine, thymine, and uracil. The negative and positive ΔG values for gas and water media, respectively, represent the spontaneity and non-spontaneity of the interactions of BN-drug with nucleobases in gas and water media. Electron charge transfer (ECT) analysis for elucidation of electron donor and acceptor effect of BN drug in gas media and donor effect in water media is given. Additionally, AIM, RDG, and hydrogen bond energy (EHB) analyses consistently confirm the presence of weak hydrogen bonding interactions between BN and nucleobases in gas and water media. Importantly, our computational results elucidate the preferential binding of BN-drug to cytosine and guanine nucleobases, providing valuable insights into the underlying mechanisms governing drugtarget cell interactions.
