Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development

A topoisomerase‐DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)‐DNA covalent complex (EctopoIcc) for molecular simulations, which is very useful in the development of new antibacterial drugs. To demonstrate the usefulness of our approach, we used a model small molecule (SM), NSC76027, obtained from virtual screening. We examined the direct binding of NSC76027 to EctopoI as well as inhibition of EctopoI relaxation activity of this SM via experimental techniques. We then performed molecular dynamics (MD) simulations to investigate the dynamics and stability of EctopoIcc and EctopoI‐NSC76027‐DNA ternary complex. Our simulation results show that NSC76027 forms a stable ternary complex with EctopoIcc. EctopoI investigated here also serves as a model system for investigating a complex of topoisomerase and DNA in which DNA is covalently attached to the protein. Targeting topoisomerase‐DNA covalent complex: This report presents an approach to design functionally important covalent complexes between bacterial topoisomerase and DNA for molecular simulations. This approach is very useful in the development of new antibacterial drugs. Our results demonstrate the suitability of the model and procedures used in this work for computational studies of inhibitors that target topoisomerases.