Computational Insight into the Mechanism of Action of DNA Gyrase Inhibitors; Revealing a New Mechanism.

Background: Discovery of novel antimicrobial agents is in need to deal with antibiotic resistance. Elucidating the mechanism of action for established drugs contributes to this endeavor. DNA gyrase is a therapeutic target used in the design and development of new antibacterial agents. Selective antibacterial gyrase inhibitors are available; however, resistance development against them is a big challenge. Hence, novel gyrase inhibitors with novel mechanisms are required.

Objective: The aim of this study is to elucidate mode of action for existing DNA gyrase inhibitors and to pave the way towards discovery of novel inhibitors.

Methods: In this study, the mechanism of action for selected DNA gyrase inhibitors available was carried out through molecular docking and molecular dynamics (MD) simulation. In addition, pharmacophore analysis, density functional theory (DFT) calculations, and computational pharmacokinetics analysis of the gyrase inhibitors were performed.

Results: This study demonstrated that all the DNA gyrase inhibitors investigated, except compound 14, exhibit their activity by inhibiting gyrase B at a binding pocket. The interaction of the inhibitors at Lys103 was found to be essential for the binding. The molecular docking and MD simulation results revealed that compound 14 could act by inhibiting gyrase A. A pharmacophore model that consisted of the features that would help the inhibition effect was generated. The DFT analysis demonstrated 14 had relatively high chemical stability. Computational pharmacokinetics analysis revealed that most of the explored inhibitors were estimated to have good drug-like properties. Furthermore, most of the inhibitors were found to be non-mutagenic.

Conclusion: In this study, mode of action elucidation through molecular docking and MD simulation, pharmacophore model generation, pharmacokinetic property prediction, and DFT study for selected DNA gyrase inhibitors were carried out. The outcomes of this study are anticipated to contribute to the design of novel gyrase inhibitors.