Dynamic profiling and binding affinity prediction of NBTI antibacterials against DNA gyrase enzyme by multidimensional machine learning and molecular dynamics simulations

Kokot, Maja (author), Minovski, Nikola (author)

Bacterial type II topoisomerases are well-characterized and clinically important targets for antibacterial chemotherapy. Novel bacterial topoisomerase inhibitors (NBTIs) are a newly disclosed class of antibacterials. Prediction of their binding affinity to these enzymes would be beneficial for de novo design/optimization of new NBTIs. Utilizing in vitro NBTI experimental data, we constructed two comprehensive multidimensional DNA gyrase surrogate models for Staphylococcus aureus (q$^2$ = 0.791) and Escherichia coli (q$^2$ = 0.806). Both models accurately predicted the IC$_{50}$s of 26 NBTIs from our recent studies. To investigate the NBTI’s dynamic profile and binding to both targets, 10 selected NBTIs underwent molecular dynamics (MD) simulations. The analysis of MD production trajectories confirmed key hydrogen-bonding and hydrophobic contacts that NBTIs establish in both enzymes. Moreover, the binding free energies of selected NBTIs were computed by the linear interaction energy (LIE) method employing an in-house derived set of fitting parameters (α = 0.16, β = 0.029, γ = 0.0, and intercept = −1.72), which are successfully applicable to DNA gyrase of Gram-positive/Gram-negative pathogens. Both methods offer accurate predictions of the binding free energies of NBTIs against S. aureus and E. coli DNA gyrase. We are confident that this integrated modeling approach could be valuable in the de novo design and optimization of efficient NBTIs for combating resistant bacterial pathogens.

• Language: English
• Keywords: bacteria, genetics, ligands, peptides, proteins, screening assays
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 18278–18295
• Numbering: Vol. 9, iss. 16
• PID: 20.500.12556/RUL-156062
• UDC: 577
• ISSN on article: 2470-1343
• DOI: 10.1021/acsomega.4c00036
• COBISS.SI-ID: 192354563
• Publication date in RUL: 06.05.2024

Record is a part of a journal

• Title: ACS omega
• Shortened title: ACS omega
• Publisher: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: biokemija, bakterije, topoizomeraze tipa I, zdravila, DNK, molekularna dinamika, Escherichia coli

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0017
• Name: Modeliranje kemijskih procesov in lastnosti spojin

• Funder: ARRS - Slovenian Research Agency
• Funding programme: Young researchers
• Project number: 39010