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Computational study of fluoroquinolone binding to Mg ( H 2 O ) N 2 + and its applicability to future drug design
Author(s) -
Bridle Mark J.,
Janesko Benjamin G.
Publication year - 2017
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.25428
Subject(s) - chemistry , affinities , binding affinities , combinatorial chemistry , protonation , magnesium , computational chemistry , pharmacophore , binding site , molecule , density functional theory , antibacterial activity , zeta potential , antibiotics , drug , hydrogen bond , stereochemistry , bacteria , pharmacology , nanotechnology , organic chemistry , biochemistry , nanoparticle , receptor , materials science , medicine , ion , biology , genetics
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 2+ 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 ) N 2 +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.