Exploring the binding mode of triflamide derivatives at the active site of Topo I and Topo II enzymes: In silico analysis and precise molecular docking

Abstract: The DNA topoisomerase enzymes, Topo I and Topo II, have been used as molecular targets for drug design of anticancer agents. The search is for new anticancer therapies that respond to the toxicity of current drug treatments and tumor resistance. The present study provides insights into a likely dual inhibitory effect on Topo I and II of trifluoromethylsulfonamide (triflamide) derivatives by computational docking studies. The physicochemical properties of these compounds were evaluated by Lipinski’s rules. Molecular docking simulations were conducted to determine the possible molecular target, mode and energy binding of the triflamide derivatives. An in silico analysis indicated that the triflamide derivatives interact with amino acid residues at the active site of Topo I and Topo II. The highest binding energy for the Topo I complex was shown by 1g and for the Topo II complex by 1e; these studies were validated by the analysis of decoys. Virtual mutations of Topo I and Topo II were tested, revealing the importance of certain active site residues on the binding mode and binding energy of the test triflamide derivatives. Overall, the results suggest that the compounds 1g and 1e could be drugs promising for the future design and development of anticancer agents. Graphic abstract: Analysis of physicochemical, toxicological and pharmacokinetic properties of triflamide derivatives and their interactions with DNA topoisomerase I and II enzymes (Topo I and II) have been reported in this study. These computational results indicated that triflamide derivatives could present a dual inhibition by binding to the active site of both enzymes, validated by decoys analysis. On the other hand, the generation of virtual mutants of Topo I and II demonstrated the great influence of certain amino acids on the mode of union of triflamides.[Figure not available: see fulltext.]