QSAR, Molecular Docking, and Pharmacokinetic Studies of 1,8-Naphthyridine Derivatives as Potential Anticancer Agents Targeting DNA Topoisomerase II

This study aimed to design novel 1,8-naphthyridine derivatives as potential anticancer agents that target topoisomerase II via a ligand-based drug design strategy. We developed a robust quantitative structure–activity relationship model via multiple linear regression, achieving a coefficient of determination ( R 2 ) of 0.6991. External validation demonstrated high predictive ability, with Q 2 (F1) and Q 2 (F2) scores of 0.8683 and 0.8670, respectively, indicating substantial reliability in predicting the biological activity of new compounds. Our dataset includes 23 analogs of 1,8-naphthyridine derivatives. The 2-dimensional structures of these compounds were drawn via ChemDraw 15.0 and optimized via density functional theory with the B3LYP hybrid functional approach via Spartan 14.1. Molecular descriptors were calculated via PaDEL software and further processed via Data Pretreatment Software V.WPS 1.2. The Kennard–Stone algorithm in the dataset division graphical user interface 1.2 split the dataset into training and test sets. Docking studies against the DNA topoisomerase II receptor (Protein Data Bank ID: 1ZXM) revealed substantial interactions, with all the newly designed ligands ( L1 to L5 ) exhibiting superior binding affinities (−9.3 to −8.9 kcal/mol) compared with the existing datasets and the standard drug bevacizumab (−6.0 kcal/mol). The pharmacokinetic evaluation revealed zero violations of Lipinski’s rule of five. Hence, further in-depth in vitro and in vivo investigations are recommended to validate these theoretical findings.