Affiliation:
1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suleyman Demirel University, Isparta, Turkey
2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cyprus Health and Social Sciences University, Guzelyurt, Northern Cyprus
Abstract
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.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Molecular Medicine,General Medicine
Cited by
3 articles.
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