Computational study of fluoroquinolone binding to Mg(H2O)N2+ and its applicability to future drug design

Abstract

Fluoroquinolones are an important therapeutic class in the targeting of new and resistant bacterial infections. Fluoroquinolones bind to bacterial type II topoisomerase via a water-Mg 21 bridge.However, binding to magnesium-containing molecules outside of the target cells increases the minimum inhibitory concentration (MIC) and promotes drug resistance. As a result, fluoroquinolones are counter-indicated with magnesium and multivalent metal cation containing drugs, such as antacids. The antibiotic efficacy of fluoroquinolones has also been shown to be pH dependent, as we show the effect of protonation state on magnesium binding. This work presents a systematic computational study of fluoroquinolones' magnesium-binding properties. We use B3LYP density functional theory and triple-zeta basis sets, to evaluate Mg H 2 O ð Þ 21 N binding affinities. Complexation is predicted to be thermodynamically favorable at neutral and basic compared to acidic pH. The calculated complexation energies broadly capture experimental binding affinities, suggesting this is a valid approach for designing new fluoroquinolones with a target magnesium binding affinity. We also investigate the effect of chemical substitution at the carboxylic acid to help in the identification of potential new antibiotics based on the fluoroquinolone pharmacophore. K E Y W O R D S binding affinity, computational, fluoroquinolones, metal complexes 1 | I N T R O D U C T I O N Fluoroquinolones are a class of broad spectrum antibiotic drugs based on the general quinolone pharmacophore, fluorinated at carbon R 6 (Figure 1). FIG URE 1 Essential fluoroquinolone structure Int J Quantum Chem. 2017;117:e25428.

Ciprofloxacin Release and Corrosion Behaviour of a Hybrid PEO/PCL Coating on Mg3Zn0.4Ca Alloy

“…The loaded PCL film reveals a burst release of ~50% of the entire load during the first 2 h of immersion followed by the release of the remaining load (up to 80–97% of the total) over 48 h. However, in the case of HCC + CIP, a gradual release over time is observed, with only 64% of the load released over the period of 240 h. The possible reason of this may be associated with the fact that Mg 2+ and Ca 2+ cations, liberated from the HHC and the substrate, are chelating with CIP 0 (zwitterionic form, Figure S3 ) leading to the formation of insoluble chelates in the physiological medium [ 19 ] and reducing the CIP release. This observation is in good agreement with other reports where the complexation of different cations present in physiological media with CIP was shown, reducing the bioavailability of the drug [ 20 , 21 ]. However, in the present work it stands to reason that the amounts of Mg 2+ (0.7 mM) and Ca 2+ (1.8 mM) initially present in the inorganic part of α-MEM are not enough for significant chelation, since after 240 h in inorganic α-MEM, the CIP release from PCL+CIP film on glass was >80%, while for HCC + CIP it was 64%.…”

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study

“…An early example from Aristilde et al discloses molecular dynamics (MD) simulations of ciprofloxacin in aqueous solvent and investigates the stability of complexes formed between ciprofloxacin and sodium, potassium, calcium, magnesium, and iron(II) [ 36 ]. Recent examples include DFT computations by Bridle et al modeling pH-dependent complexes of ciprofloxacin and magnesium in aqueous solution [ 37 ], and an experimental and computational study of ciprofloxacin derivatives complexed with copper(II) [ 38 ].…”

Hierarchical Hybrid Coatings with Drug-Eluting Capacity for Mg Alloy Biomaterials

“…BF-PCL films revealed a burst release during the first hour of immersion followed by a further release of the remaining load up to ~90% in 96 h. However, for the loaded Mg-HHC system, a rather gradual elution was observed over the time, with only 20 and 40% of PAR and CIP loads released after 10 days, respectively. This may be associated with the formation of insoluble chelates between Mg 2+ and Ca 2+ and CIP 0 or PAR 0 (Zwitterionic) in the medium [34][35][36][37], reducing the PAR and CIP release. This is in agreement with the observation of other previous reports where the complexation of different cations with CIP and PAR structures has been shown to reduce bioavailability [38,39].…”