DFT- and Multiwfn-driven investigation of 1-benzofuran: Structural, topological, natural bond orbital, Hirshfeld surface, and interaction energy analyses, coupled with molecular docking of pyrazole and chalcone for anti-breast cancer exploration

Cancer remains a major global health concern, with current treatments often limited by side effects, resistance, and low efficacy. This study investigates the anticancer potential of 1-benzofuran, a bioactive heterocycle, through a combination of computational techniques. Structural, topological, natural bond orbital, Hirshfeld surface, and interaction energy analyses were performed using Density Functional Theory (DFT) and Multiwfn, alongside molecular docking simulations via AutoDock Vina. Geometry optimization was conducted using semi-empirical (MP6), Hartree–Fock/B3LYP, and density functional theory/B3LYP approaches with basis sets including 6-31+G(d,p), 6-311+G(d,p), and aug-cc-pVDZ in both gas and aqueous media. The results revealed significant solvent-induced structural changes, such as a reduction in the C(3)–C(4) bond length and an increase in the C(6)–C(5) bond, along with enhanced dipole moment and electron delocalization. Oxygen (O1) showed a strong negative charge (−0.562 51), and interaction energies were higher in water (24.65 kcal/mol) than in gas (20.28 kcal/mol), suggesting increased stability and reactivity under physiological conditions. Hirshfeld analysis confirmed stronger intermolecular interactions in aqueous media. Molecular docking showed favorable binding of 1-benzofuran to 6NMO (−5.7 kcal/mol), which improved upon conjugation with pyrazole and chalcone, reaching −7.9 kcal/mol against 8G2M. This highlights the multi-ligand strategy’s effectiveness in enhancing anticancer potential.