Computational Design and Molecular Docking of Perimidine–Peptide Hybrids as Next-Generation Topoisomerase IIα Inhibitors

Abstract

The growing problem of antimicrobial resistance (AMR) highlights the urgent need for new antibiotics with innovative structures and mechanisms. In this study, we explored the design and computational evaluation of perimidine–peptide hybrids as potential inhibitors of human Topoisomerase IIα, which serves as a model for bacterial Type II topoisomerases. Using structure-based molecular docking, we tested five carefully designed perimidine derivatives (pk1–pk5) using AutoDock Vina. To validate the docking protocol, we compared it with the known inhibitor etoposide (PDB: 1ZXM), achieving an RMSD of 0.89 Å, confirming the reliability of the method. Among the tested compounds, pk4 showed the best binding energy (-12.1 kcal/mol), outperforming etoposide. Interaction analysis revealed key bonding interactions such as π–π stacking, salt bridges, and metal coordination with catalytic residues and a magnesium ion. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling suggested that pk4 has favorable pharmacokinetic properties and a safe toxicity profile, making it a strong candidate for further development. This study offers a computational approach for designing novel antibiotics and identifies a promising scaffold for experimental testing.