Orientation of oxazolidinones in the active site of monoamine oxidase

T.Z.E. Jones, P. Fleming, C.J. Eyermann, M.B. Gravestock, Rona Ruth Ramsay

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21 Citations (Scopus)


Oxazolidinone inhibitors of monoamine oxidase (MAO) and oxazolidinone antibacterials are two distinct classes of drug, often with linear structures and overlapping activities for some derivatives. By synthesizing novel dimerised derivatives with identical substitution of the two C-5 side chains, we have obtained experimental evidence for the orientation of oxazolidinones in the active site of MAO A. Two types of spectral changes, either increasing the absorbance at 5 10 nm or decreasing it at 495 nm depending on the group nearest to the flavin cofactor, were seen on ligand binding to MAO A. Side chain derivatives with amine substituents are very poor substrates so that it was possible to examine the spectral change due to binding of a substrate before reduction of the flavin occurred. Binding of these amino derivative substrates to MAO A induced a spectral change characterized by a strong decrease in absorbance at 495 nm. These substrates reduced the enzyme fully without any trace of a semiquinone intermediate. Only oxazolidinone inhibitors with a bromo-imidazole substituent increased the yield of semiquitione intermediate obtained during chemical reduction. In accord with the experimental data, results of docking experiments showed that binding of the oxazolidinone ring in the aromatic cage close to the flavin was favored and that the nitrogen of the derivatives that were substrates was within van der Waals distance of N-5 of the flavin. (c) 2005 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)407-416
Number of pages10
JournalBiochemical Pharmacology
Issue number3
Publication statusPublished - 1 Aug 2005


  • oxazolidinone
  • monoamine oxidase
  • difference spectra
  • flexible docking
  • kinetics


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