Identification of potential Escherichia coli DNA gyrase B inhibitors targeting antibacterial therapy: an integrated docking and molecular dynamics simulation study

Abstract

The alarming rise in the rate of antibiotic resistance is a matter of significant concern. DNA gyrase B (GyrB), a critical bacterial enzyme involved in DNA replication, transcription, and recombination, has emerged as a promising target for antibacterial agents. Inhibition of GyrB disrupts bacterial DNA replication, leading to cell death, making it an attractive candidate for antibiotic development. Although several classes of antibiotics targeting GyrB are currently in clinical use, the emergence of antibiotic resistance necessitates the exploration of novel inhibitors. In this study, we aimed to identify potential Escherichia coli GyrB inhibitors from a database of phytoconstituents sourced from Indian medicinal plants. Utilizing virtual screening, we performed a rigorous search to identify compounds with the most promising inhibitory properties against GyrB. Two compounds, namely Zizogenin and Cucurbitacin S, were identified based on their favorable drug likeliness and pharmacokinetic profiles. Employing advanced computational techniques, we analyzed the binding interactions of Zizogenin and Cucurbitacin S with the ATP-binding site of GyrB through molecular docking simulations. Both compounds exhibited robust binding interactions, evidenced by their high docking energy scores. To assess the stability of these interactions, we conducted extensive 100 ns molecular dynamics (MD) simulations, which confirmed the stability of Zizogenin and Cucurbitacin S when bound to GyrB. In conclusion, our study highlights Zizogenin and Cucurbitacin S as promising candidates for potential antibacterial agents targeting GyrB. Experimental validation of these compounds is warranted to further explore their efficacy and potential as novel antibiotics to combat antibiotic-resistant bacteria.

Communicated by Ramaswamy H. Sarma

Keywords:

• DNA gyrase B
• antibacterial resistance
• Zizogenin
• Cucurbitacin S
• virtual screening
• molecular dynamics simulations

Acknowledgments

Reem Binsuwaidan extends her appreciation to Princess Nourah bint Abdulrahman University Researchers Supporting Project Number PNURSP2023R304, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

Authors’ contributions

Bader S. Alotaibi: Conceptualization, Formal analysis, Writing – Original Draft, Writing – Review & Editing. Mohammed Ageeli Hakami: Methodology, Software, Formal analysis, Data curation, Writing – Original Draft, Writing – Review & Editing. Talha Jawaid: Writing – Original Draft, Writing – Review & Editing. Nawaf Alshammari: Methodology, Investigation, Visualization, Validation, Writing – Original Draft, Writing – Review & Editing. Reem Binsuwaidan: Writing – Review & Editing. Mohd Adnan: Conceptualization, Formal analysis, Data curation, Review & Editing.

Disclosure statement

Authors declare that there is no conflict of interest.

Additional information

Funding

This work is supported by Princess Nourah bint Abdulrahman University Researchers Supporting Project Number PNURSP2023R304, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.