Abstract
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.
Highlights
DNA topoisomerases are responsible for regulation of DNA topology, a crucial cellular process, which is very important in replication, transcription and recombination.[1]
We considered NSC76027, one of the top hit small molecule (SM) based on affinity obtained from virtual screening (VS) that lie near the active site, as a model SM just to demonstrate the usefulness of our approach in the new antibacterial drug development
Trapping transient covalent complex of DNA Topoisomerase I (topoI) and DNA in bacterial cells using topoI poison inhibitors leads to accumulation of such complexes, which kills the bacterial cells
Summary
DNA topoisomerases are responsible for regulation of DNA topology, a crucial cellular process, which is very important in replication, transcription and recombination.[1]. Previous genetic studies showed that the accumulation of the topoI-DNA covalent cleavage complexes (topoccs) in Escherichia coli can cause the bacterial cell death.[7] Bacterial DNA topoI belonging to the type IA topoisomerase family maintains the genome stability[8] and is a promising target biomolecule for antibacterial drug discovery[7a, 9] with E. coli topoisomerase I (EctopoI) as the most extensively studied member of the type IA topoisomerase family.[10] In EctopoI, Y319 is the active site tyrosine, which is responsible for the formation of transient covalent linkage with the 5’ phosphoryl group of cleaved DNA.[11] In E. coli, EctopoI regulates the DNA supercoiling by removing excess negative supercoils.[12] In recent years, bacterial pathogens have become more resistant to available antibacterial drugs, becoming a serious public health issue. It is highly desirable to identify the poison inhibitors for type IA topoI for the development of new antibacterial drugs.[3, 7a, 9a] Development of such new antibacterial drugs requires investigations of topoIccs
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