eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2026-03-20 19 1 191 204 10.13005/bpj/3347 71129 article Mehribon Pirimova 1 Masud Karimov 2 Djalilov Abdulahat 2 Feruz Ismoilov 2 Muparrax Xodjayeva 1 Oybek Sultonov 2 Department of Medical and Biological Chemistry, Tashkent State Medical University, Tashkent, Uzbekistan Tashkent Chemical and Technological Scientific Research Institute, Tashkent, Uzbekistan Pyridine-2-carbothioamide and its Co(II), Ni(II), and Cu(II) complexes were evaluated as potential inhibitors of the ATPase domain of human topoisomerase IIα using an integrated density functional theory (DFT) and molecular docking approach. Geometry optimization and electronic-structure calculations showed that metal coordination markedly altered the frontier orbital distribution of the parent ligand, reduced the HOMO–LUMO energy gap, and increased global softness and electrophilicity. Docking simulations within the ATPase nucleotide-binding pocket indicated that all metal complexes displayed stronger predicted binding than the free ligand. Among the investigated systems, the Cu(II) complex exhibited the most favorable docking score and the richest interaction network with key active-site residues, including His120, Arg142, and Phe101. The observed trend suggests that coordination-induced electronic modulation contributes to enhanced binding capability within the catalytic pocket. Overall, the results identify pyridine-2-carbothioamide-based transition-metal complexes, particularly the Cu(II) derivative, as promising candidates for further experimental investigation as topoisomerase IIα-targeted metallodrugs. These findings provide a theoretical basis for the rational design of Topoisomerase IIα-targeted metallodrugs and highlight the importance of coordination-induced electronic modulation in enhancing ligand–protein interactions. https://biomedpharmajournal.org/vol19no1/molecular-docking-and-dft-based-evaluation-of-pyridine-2-carbothioamide-first-row-transition-metal-complexes-targeting-topoisomerase-ii%ce%b1/ Anticancer agents Density functional theory Molecular docking Pyridine-2-carbothioamide complexes Structure–activity relationship Topoisomerase IIα.