Date of this Version
4-3-2020
Document Type
Article
Rights
default
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.
DOI
10.1002/cmdc.201900721
Identifier
32043806
Recommended Citation
Tiwari PB, Chapagain PP, Seddek A, Annamalai T, Üren A, Tse-Dinh YC. Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development. ChemMedChem. 2020 Apr 3;15(7):623-631. doi: 10.1002/cmdc.201900721. Epub 2020 Mar 18. Erratum in: ChemMedChem. 2021 Jun 18;: PMID: 32043806; PMCID: PMC7133791.
Rights Statement
In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/
This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
Comments
ChemMedChem. Author manuscript; available in PMC 2021 Apr 3. Published in final edited form as: ChemMedChem. 2020 Apr 3; 15(7): 623–631. Published online 2020 Mar 18. doi: 10.1002/cmdc.201900721