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

Kokot, Maja (avtor), Minovski, Nikola (avtor)

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.

• Jezik: Angleški jezik
• Ključne besede: bacteria, genetics, ligands, peptides, proteins, screening assays
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: Str. 18278–18295
• Številčenje: Vol. 9, iss. 16
• PID: 20.500.12556/RUL-156062
• UDK: 577
• ISSN pri članku: 2470-1343
• DOI: 10.1021/acsomega.4c00036
• COBISS.SI-ID: 192354563
• Datum objave v RUL: 06.05.2024

Gradivo je del revije

• Naslov: ACS omega
• Skrajšan naslov: ACS omega
• Založnik: American Chemical Society
• ISSN: 2470-1343
• COBISS.SI-ID: 525873945

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: biokemija, bakterije, topoizomeraze tipa I, zdravila, DNK, molekularna dinamika, Escherichia coli

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0017
• Naslov: Modeliranje kemijskih procesov in lastnosti spojin

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Program financ.: Young researchers
• Številka projekta: 39010